Medchem exam 2
Axon Terminal
(terminal boutons; presynaptic terminals) - swelling of axon at its terminal end, enriched with vesicles containing neurotransmitter - forms "synaptic contact" with receptive region of a second neuron (i.e. a postsynaptic neuron - swellings filled with vesicles can also occur along length of axon giving rise to a beaded appearance (these swellings are called varicosities); may form synapses
A.Glutamic acid (glutamate)
•Reuptake (GLT) •Transport into glial cells (GLT/GLAST) •Conversion to glutamine (GS) •Transport into GABAergic neuron (SAT) •Package into vesicles (VGLUT) (answer 66)
000
1) Inactive tyrosine kinase domains (TKDs) are autoinhibited in cis by the juxtamembrane (JM) region. 2) Ligand binding induces a dimeric receptor assembly. 3) Conformational changes within "D" domains induce interactions between the intracellular regions that alleviate juxtamembrane inhibition 4) This event promotes transactivation of the TKDs (answer = 000)
Downstream response - NGF receptor
1) Nerve growth factor (NGF) activates neuronal differentiation and survival. 2) As other RTKs, NGF activates MAP kinase pathway and PI3 kinase pathway. **In reality, these pathways may entangle each other further downstream for cross signaling events**
Downstream response of Cytokine receptors
1) STAT reaches the nucleus 2) it binds to a consensus DNA-recognition motif called gamma-activated sites (GAS) in the promoter region of cyt.okine-inducible genes and 3) transcription is activated 4) The STAT protein can be dephosphorylated by nuclear phosphatases, which leads to inactivation of STAT and subsequent transport out of the nucleus by an exportin-RanGTP complex.
Downstream response explanation
1) hormone enters cell 2) Hormone binds to Ligand binding domain 3) the binding of that domain kicks out the HSP 4)Nuclear Receptor + hormone complex then undergoes further dimerization so that it can go through the nuclear pore 5) once it enters the nucleus from the nuclear pore, it can act as a transcription factor and result in mRNA
Downstream response - Insulin Receptor
1) ligan binds to insulin receptor 2) the receptor phosphorylates 3) GLUT4 is transported to the surface (when inactive, not much GLUT4 at surface -- when active, a lot of GLUT4 is recruited by the receptor 4) Glut4 transports glucose molecules inside the cell
Key steps in signal transduction
1)Release of the primary messenger (i.e., GPCR ligand) 2)Reception of the primary messenger, signal molecule binds to receptor 3) Relay: modulation by other factors 4) Amplification 5) Delivery of the message inside the cell by the second messenger to multiple targets
-action potenital -Depolarization -Ca+ -exocytosis -postsynaptic receptor -ion channel -depolarization -hyper-polarization -terminatjon re-upotakee --- degredation
1. Arrival of ___________ at axon terminal 2. ____________ of axon terminal membrane 3. Influx of _______ into terminal via voltage-gated Ca++ channels 4. Fusion of vesicles with terminal membrane 5. Extrusion of vesicle contents into synapse: ___________ 6. Binding of transmitter to _____________ 7. Opening of chemically-gated _______________ 8. Change in membrane potential: -EPSP if Na+ channels open (________________) -EPSP if K+ or Cl- channels open (___________________) 9. _____________ of transmitter action by __________ into presynaptic terminal, or by enzymatic ____________, or both
The SNARE Cycle
1. Synaptobrevin interacts with two plasma membrane target proteins, the transmembrane protein syntaxinand the peripheral membrane protein SNAP-25. 2.The three proteins form a tight complex bringing the vesicle and presynaptic membranes in close apposition (see part B). Munc18 binds to the SNARE complex. 3.Calcium influx triggers rapid fusion of the vesicle and plasma membranes; the SNARE complex now resides in the plasma membrane. 4.Two proteins, NSF and SNAP (unrelated to SNAP-25), bind to the SNARE complex and cause it to dissociate in an ATP-dependent reaction.
Transcription-activating domain
3 Domains of Nuclear Receptors - Glucocorticoid receptor activates transcription
DNA binding domain
3 Domains of Nuclear Receptors - Glucocorticoid receptor binds DNA
Ligand binding domain
3 Domains of Nuclear Receptors - Glucocorticoid receptor binds glucocorticoid
Olanzapine
5-HT2A >H1 >D4 >D2 >α1 >D1 α - alpha adrenergic, H - Histamine, 5-HT - serotonin, D - dopamine, M - muscarinic
- monosodium glutamate (MSG, food additive, flavor enhancer) - kainic acid (a potent neurotoxin used as research tool; excites neurons to death)
A. Glutamic acid (glutamate) Important receptor agonist::
by high affinity retake transporters (several major families known)
A. Glutamic acid (glutamate) Inactivation:
increases in membrane cation (Na+ and Ca++) permeability thereby depolarizing neuronal membrane
A. Glutamic acid (glutamate) Mechanism of action (ion channel receptors):
-NMDA (N-methyl-D-asparte) -AMPA -kainate
A. Glutamic acid (glutamate) Receptor subtype: Ligand-gated ion channel receptors
-mGluR 1-8. "metabotropic" glutamate receptors -GPCRs
A. Glutamic acid (glutamate) Receptor subtype: coupled G protein / second messengers
-dietary amino acid -neurons from precursor glutamine
A. Glutamic acid (glutamate) Synthesis:
none clinically available yet, but several in clinical trials (an area of intensive research interest; antagonists are of potential therapeutic value for stroke, epilepsy, and other illnesses caused by excessive neuronal excitability)
A. Glutamic acid (glutamate) receptor antagonist::
-inhibitory postsynaptic potential (IPSP) -excitatory potential
B. An inhibitory pathway (I) generates a small hyperpolarizing current called an _________________________. On the right, if the previously suprathreshold excitatory input (E3) is given shortly after the inhibitory input (I), the IPSP prevents the __________________ from reaching threshold.
similar to GABA (increases Cl- conductance)
B. Glycine Mechanism of action :
strychnine
B. Glycine Receptor antagonist :
serotonin --- dopamine -schizophrenia --- EPS -water soluble
Benzisoxazoles: Risperidone -A benzisoxazole derivative with uniquely balanced __________ / ___________ antagonism. -Has improved efficacy vs. both +/- symptoms of ____________________ and reduced ____________. -HCl salt formation of piperidine ring nitrogen results in _____________ compound for oral formulation
Phosphorylation
Insulin Receptor , __________________ promotes GLUT4 translocation to the cell membrane
GLUT4
Insulin Receptor _______________ mediates glucose transport across the cell membrane
2 chainz
Insulin peptide made of _________
type 2 diabetes mellitus
Insulin resistance contributes to the pathogenesis of ____________________________
H12 --- coactivator
Binding of an antagonist induces a conformation change in ________ that blocks _________ binding
-sublingual -D2 --- 5-HT2A -limited --- hyperlipidemia --- prolactin -minor
Current clinical practice Asenapine -administered by ______________ route -blocks ____ and ___________ receptors -____________ weight gain and NO _____________; NO changes in ____________ - extrapyramidal effects _________ (low percentage of patients experience akathisia)
-tardive dyskinesia -drug-resistant -agranulocytosis
Current clinical practice Clozapine -may even suppress ___________________ due to other agents -effective even in _____________________cases, reduces positive and negative symptoms -most serious side-effect: ________________________ in 2% of patients -mechanism uncertain
blocks
Current clinical practice Clozapine __________________ many receptors besides DA receptors (e.g. muscarinic, 5-HT2A, α1-adrenergic and histamine H1 receptors): affinities, D4 = α1 > 5HT2A > D2 = D1
5HT7 --- high -benign
Current clinical practice Lurasidone -blocks 5HT2A and D2 receptors as well as ____________ receptors with ___________ affinity -______________ metabolic profile; minimal weight gain, no lipid changes extrapyramidal effects may occur, esp. akathisia
weight gain ---metabolic
Current clinical practice Olanzapine _______________ and associated _________________ disorder (diabetes, hypertension, hyperlipidemia)
D2 --- D4 --- 5-HT2A
Current clinical practice Olanzapine antipsychotic effect is thought to be mediated by ______, ________, and ________
positive --- negative edxtrapyramidal
Current clinical practice Olanzapine effective in treating both ___________ and ______________ symptom -slow incidence of _______________ effectsmain side-effects: weight gain and associated metabolic disorder (diabetes, hypertension, hyperlipidemia)
-low incidence --- weight gain
Current clinical practice Quetiapine receptor blocking profile: H1> α1 > D2 > 5-HT2A -effective antipsychotic with_____________ of extrapyramidal side-effects and a lesser tendency to induce _____________ -effective for both positive and negative symptoms
clozapine
Current clinical practice Risperidone -antipsychotic profile without the blood toxicity of ____________
extrapyramidal ---- tardive dyskinessia
Current clinical practice Risperidone lower incidence of ______________ side effects and ________________ than classical antipsychotics when drug is used in low doses
prolongation --- cardiac
Current clinical practice Ziprasidone may cause QTc segment ___________________ and serious ___________ arrhythmias (ventricular tachycardia and sudden death) -blocks 5-HT2A and D2 receptors like other atypical drugs
Risperidone
Current clinical practice ______________ generally not as effective in drug-resistant cases as is clozapine??
-AMPA, Kainate, and NMDA -4 subunits
Ionotropic glutamate receptor (cation) (3 of them) ---- and how many subunits ?
multiple
Is there one particular gene involved, or multiple genes involved in Schizophrenia ?
inside --- outside
K+ typically moves from __________ the cell to _________ the cell
benzodiazepines
LGIC -- GABA Receptors -_______________________ are positive allosteric modulators that enhance the effect of GABA at the GABAA receptor
Benzodiazepines
LGIC -- GABA Receptors ____________________ have sedative, hypnotic (sleep- inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties.
Barbiturates --- benzodiazepines
LGIC -- GABA Receptors ____________________ were used as anxiolytics and hypnotics, but have been largely replaced by ______________________ which have less potential for lethal overdoses.
Locus ceruleus
Norepinephrine Neurons ___________________________- 1500 neurons located in the pons area; 5 major noradrenergic tracts, project to many brain areas
-cytoplasm --- nucleus -dissociate --- dimerize
Nuclear Receptors These receptors are located in either the _________________ or _____________, in a complex with chaperone proteins Upon binding agonist the chaperone proteins ______________ and receptors ____________ either with themselves or another nuclear receptor
-specific genes -development --- homeostasis ---metabolism
Nuclear Receptors: -regulates the expression of ______________ -participate in control of ____________, ______________, _________________
DNA
Nuclear Receptors: Can directly bind ___________(classified as transcription factor)
adenylate cyclase (AC) --- decreases
Once the G protein Gi is activated, it inhibits __________________, and will _____________ the cAMP
adenylate cyclase (AC) --- increases
Once the G protein Gs is activated, it couples to __________________, and will cyclize and ______________ the cAMP
-Partial agonist of D2 -Partial agonism of 5HT1A -Antagonism of 5HT2A
Order of binding affinity for CNS neurotransmitter receptors Aripiprazole
D2 > D1 ~/= 5HT2 > α1
Order of binding affinity for CNS neurotransmitter receptors butyrophenones
D2 ~D1 > α1 ~/= 5HT2
Order of binding affinity for CNS neurotransmitter receptors phenothiazines
D2 ~/= 5HT2 (improvement of negative symptoms) >>> D1 > α1
Order of binding affinity for CNS neurotransmitter receptors risperidone, clozapine
Huntington's disease --- Gilles de la Tourette's syndrome
Other clinical uses of DA receptor antagonists Treatment of _________________ and ______________
antiemetic agents
Other clinical uses of DA receptor antagonists As _______________, by blocking D2 receptors in CRTZ (especially chlorpromazine)
anesthesiology
Other clinical uses of DA receptor antagonists In ___________________: combination of droperidol and fentanyl (Innovar) to produce state of neuroleptanalgesia
hiccoughs
Other clinical uses of DA receptor antagonists Treatment of intractable _________________ - mechanism unknown
-P2X4R -3 subunits
P2X purinoreceptors (cation) (1 of them) --- and how many subunits ?
-GABAA and Glycine -5 subunits
Pentameric cas-loop anionic receptors (2 of them) --- and how many subunits ?
-5-HT and Nicotinic acetylcholine -5 subunits
Pentameric cas-loop cationic receptors (2 of them) -- and how many subunits ?
999
Peptide -Large dense-core vesicles •No transporter re-uptake•Catabolic peptidases (answer 999)
848
Peptide chart (answer 848)
opioid receptors
Peptide transmitter main receptor of Enkephalins and endorphins are ____________________
-DA transmission ---- A10 mesolimbic DA neurons -linear correlation -basal ganglia ---- pituitary
Pharmacological basis of therapeutics in schizophrenia Goal has been to reduce ________________ in terminal regions of ___________________________; all clinically used drugs block DA receptors (esp. D2-like receptors) -a___________________ exists between drugs' biochemical abilities to block D2-like DA receptors and their antipsychotic potencies therapeutic problems arise because it is difficult to selectively block DA receptors in only -limbic terminal areas; extrapyramidal and endocrine side- effects develop due to blockade of DA receptors in _____________ and _____________
-white cell count (leukopenia) -clozapine
Pharmacological effects and side effects of antipsychotics Blood disorders: 1) many antipsychotics decrease ___________________or increase certain elements (eosinophilia) 2) ____________________ can cause bone marrow suppression and frank agranulocytosis - incidence ~1% - safe use requires weekly white cell counts and rapid follow-up if symptoms of fever, malaise, cough develop during clozapine use
-prolactin secretion -breast enlargement --- amenorrhea-galactorrhea -prolactin-elevating effects -prolactin release -female -male
Pharmacological effects and side effects of antipsychotics Endocrine effects 1 increased __________________ (DA, acting via D2 receptors, normally inhibits prolactin secretion from the pituitary) -↑ prolactin causes _________________ in males, ___________________ in females -all "typical" antipsychotics as well as risperidone cause prominent ___________________ -the "atypical" antipsychotics clozapine, quetiapine, and olanzapine have minimal effects on _______________________ -increased ___________ libido -decreased ___________ libido -increased appetite, weight gain, hyperlipidemia, development of diabetes - prominent with all antipsychotics, esp. atypical drugs, clozapine and olanzapine hypothermic effect
Serotonin (5-HT2A) receptors
Pharmacological effects and side effects of antipsychotics All block DA receptors (predominantly D2 receptors); newer "atypical antipsychotics also potently block_____________________ receptors and several other receptors
Chemoreceptor trigger zone (CTZ)
Pharmacological effects and side effects of antipsychotics Antiemetic effect due to blockade of DA receptors at ____________________________ in medulla
anticholinergic
Pharmacological effects and side effects of antipsychotics Autonomic effects: 1) __________________ effects (muscarinic blockade) -cycloplegia (blurred vision), dry mouth, difficulty urinating, constipation
long term potentiation
SYNAPTIC STRENGTHENING MORE AMPA RECEPTORS (strengthens memory) -an increase in a synapse's firing potential after brief, rapid stimulation. Believed to be a neural basis for learning and memory. -postsynaptic end of neuron senses glutamate and adjust number of receptors
long term depression
SYNAPTIC WEAKENING LESS AMPA RECEPTORS -a long-term decrease in the excitability of a neuron to a particular synaptic input caused by stimulation of the terminal button while the postsynaptic membrane is hyperpolarized or only slightly depolarized
environmental --- experiential
Schizophrenia consist of genetic predisposition with variable ______________________ / _______________ contributions
-improve -relapse --- remissions -worsening
Schizophrenia is CHRONIC 1/3 of patients _________ with treatment 1/3 of patients have _____________ and _________ 1/3 of patients follow a chronically ____________ course
neurodevelopment --- 16 and 20
Schizophrenia is a _____________________ disorder that first presents clinically between the ages of __________ and ____________ years
Olanzapine
approved in 1996, now second most widely used antipsychotic pharmacological profile similar to clozapine (binds to numerous receptors: affinities 5-HT2A > H1 > D4 > D2 > α1 > D1);
Quetiapine
approved in 1997, one of the most widely used
Ziprasidone
approved in 2001, marketed in an injectable form for acute treatment of extremely agitated or violent patients
Lurasidone
approved in 2010 for schizophrenia, and in 2013 for depressive episodes associated with bipolar disorder
Asenapine
approved in August 2009 for schizophrenia and acute maniac episodes associated with bipolar disorder
Aripiprazole
approved in late 2002, now the most widely prescribed
psychoses
are severe mental disorders characterized by impaired behavior with inability to think coherently and to comprehend reality
first generation antipsychotics
phenothiazines and butyrophenones (Typical Antipsychotic)
autophosphorylation
phosphorylation of an enzyme by itself
Astrocyte
provides biochemical support of endothelial cells that form the BBB and supplies nutrients to the nervous system
Oligodendrocytes
provides the axon of long rang projection neuron insulation by a myelin sheath
second generation antipsychotics
risperidone and clozapine (Atypical Antipsychotics)
failed ---antipsychotic efficacy
several D4 selective antagonists were developed, but __________ in clinical trials as antipsychotics; D4 blockade not solely responsible for clozapine's _____________________
Glutamic acid (glutamate)
major excitatory transmitter in BRAIN
Bioisosteres
substituents or groups that have chemical or physical similarities, which produce broadly similar biological properties
Vasculature
supplies oxygen and nutrients; the brain would quickly suffer damage from any stomach in blood supply
H12
the C-terminal alpha helix of the ligand binding domain - gates coactivator binding
Clozapine
the first effective antipsychotic without extrapyramidal side-effects
calcium
too much _________ in the cell can lead to toxicity and even cell death
Arrestin-mediated receptor internalization
what inhibitory mechanism of GCPRs is this ?
Chlorpromazine:
α1 = 5-HT2A > D2 > D1 α - alpha adrenergic, H - Histamine, 5-HT - serotonin, D - dopamine, M - muscarinic
G-protein coupled (7 trans-membrane spanning receptors)
All DA receptors are _______________________
transducer
All G protein-coupled receptors use G protein as a _________________
6 --- 1
DSM-V criteria : _____ months duration with at last ___ months active phase
Catecholamines --- synthesis
Different populations of "_______________" neurons contain a specific catecholamine transmitter and the enzyme necessary for its ________
kinase domain
Dimerization of Receptor Tyrosine Kinase results in the activation of the ___________________
metabolism --- inflammation
Glucocorticoids control _____________ and decrease __________________
cationic --- excitatory synapse
Glutamine and Aspartate are linked to __________ channels (________________)
Quetiapine
H1 > α1 > M1,3 > D2 > 5-HT2A α - alpha adrenergic, H - Histamine, 5-HT - serotonin, D - dopamine, M - muscarinic
8707
Histamine chart (answer 707)
-5 -D1, D2, D3, D4, D5 (D1 and D2 discovered first --- D3 D4 D5 discovered later)
How many DA receptor subtypes are there ? and what are they ?
14 --- G coupled proteins
How many repeaters are there for Serotonin (5-hydroxytryptamine; 5-HT)? And what type are most of them (except 1)
7
How many transmembrane domain do all G protein-coupled receptors have ?
345
Imagee shows just how important and how much the G protein receptors contributes to (answer = 345)
OH
In order to convert structures into long acting neuroleptic , there MUST BE ________ to turn into an ester group -Without it, it cannot be converted into a long acting neuroleptic
locks the conformation of the receptor
What does the ligand do in a Two State-Model of receptor activation ?
The TRK has an intercellular domain that works as a kinase In the Cytokine Receptor, that domain is lacking, so that kinase needs to be recruited in order to activate the receptor (other than that, the functions are VERY similar)
What is the difference between TKRs and Cytokine Receptors ?
phosphorylate specific tyrosine residues
What is the kinase job after it is activated ?
Piperazine > piperidine > aliphatics
What is the order of the subclasses of antipsychotic phenothiazine in relation to Antipsychotic Potency from most potent to least ?
Piperazine > piperidine > aliphatics
What is the order of the subclasses of antipsychotic phenothiazine in relation to EPS Frequency from most frequent to least ?
aliphatics > piperidine > Piperazine
What is the order of the subclasses of antipsychotic phenothiazine in relation to Hypotensive Effect from strongest to weakest ?
aliphatics > piperidine > Piperazine
What is the order of the subclasses of antipsychotic phenothiazine in relation to Sedation from strongest to weakest ?
Phenothiazine heterocyclic
What is this a structure of ?
-Loxapine (X=CH3 -Amoxapine (X=H)
What is this structure ?
Clozapine
What is this structure ?
Olanzapine
What is this structure ?
Quetiapine
What is this structure ?
-Phenothiazine heterocyclic -An H+ is being added to the more basic amine, which will increase water solubility for better oral bioavailability
What molecule is it ? and What is occurring with this reaction ?
3 carbon alkyl chain (with 2 carbon side chains preferred conformation cannot be obtained)
What part of the structure of phenothiazine heterocyclic is optimal for antipsychotic activity
-50% -15% -15%
What percent concordance of Schizophrenia in identical twins? Dizygotic twins? first degree relatives?
1-3%
What percent of population has Schizophrenia
-H1 -α1 -α2 -M1 receptors -5HT2
What receptors are utilized by Phenothiazine derivatives? (6)
Thioxanthane
What structure is this ?
aliphatic
What subclasses of antipsychotic phenothiazine is this ?
piperazine (R=hydroxyethyl > alkyl)
What subclasses of antipsychotic phenothiazine is this ?
piperidine
What subclasses of antipsychotic phenothiazine is this ?
-Monoamine oxidasse (MAO) -Catechol-O-methyltransferase (COMT)
What two enzymes are involved in enzyme degradation of Catecholamines?
Stimulatory (Gs)
What type of G protein coupling does D1 and D5 utilize?
Inhibitory (Gi/o)
What type of G protein coupling does D2 and D3 and D4 utilize?
G protein coupled (Metabotropic) receptor
What type of ion channels and neurotransmitter receptors is this ?
Ligand gated ion channel
What type of ion channels and neurotransmitter receptors is this ?
Voltage gated ion channel
What type of ion channels and neurotransmitter receptors is this ?
Amines
What type of neurotransmitters are these structures ?
Amino Acids
What type of neurotransmitters are these structures ?
Endocannabinoids
What type of neurotransmitters are these structures ?
Monoamines
What type of neurotransmitters are these structures ?
Peptides
What type of neurotransmitters are these structures ?
Purines
What type of neurotransmitters are these structures ?
Insulin
What was the first hormone to be isolated and identified ?
HSP90 --- ligand
When Glucocorticoid is in its inactive state, ____(1)_______ binds to the DNA binding domain, is it cannot bind to DNA ---- and then once a ___________ binds to the ligand binding domain, the ________(1)______ gets pushed away and the DNA binding domain can bind to DNA
Heterodimers
When a receptor dimerizes another nuclear receptor
Homodimers
When a receptor dimerizes with themselves
negative
When the flow of a negative ion is inward --- the direction and sign of flux becomes _______________
positive
When the flow of a negative ion is outward --- the direction and sign of flux becomes _______________
positive
When the flow of a positive ion is inward --- the direction and sign of flux becomes _______________
negative
When the flow of a positive ion is outward --- the direction and sign of flux becomes _______________
membrane bound
Where do the receptor tyrosine kinase (RTK), Cytokine receptor, Ligand-gated ion channel receptor, G protein-coupled receptors reside ?
inside the cell
Where does the Nuclear receptor reside ?
Class A
Which class of G protein-coupled receptors has the most receptors ?
Tuberoinfundibular
Which dopamine pathway regulates the hormonal pathway, which does not have role in the psychosis?
D2
Which dopamine receptor subtype has a long 3rd intracellular loop and a short carboxyl tail
D1
Which dopamine receptor subtype has a short 3rd intracellular loop and a long carboxyl tail
First and Second
Which generation(s) of antipsychotics are antagonist ?
Third
Which generation(s) of antipsychotics are partial agonist ?
extracellular fluid
Who has more Cl- ions, Cytoplasm or extracellular fluid?
cytoplsm
Who has more K+ ions, Cytoplasm or extracellular fluid?
extracellular fluid
Who has more Na+ ions, Cytoplasm or extracellular fluid?
Glutamic acid (glutamate)
Widespread CNS distribution
D3 --- D4 --- D2-like family
____ and _____ receptors resemble D2 receptors in structure and comprise "________" family
D5 --- D1-like family
____ receptors resemble D1 receptors in structure and coupling cAMP -- they comprise "___________" family
HSP90
_____________ binding site keeps Glucocorticoid receptors from binding to DNA in thee absence of ligand
Phosphodiesterase
____________________ can inhibit the procedure and turn cAMP back to 5'-AMP
Glucocorticoids
___________________________ are used to treat: allergies asthma autoimmune diseases sepsis; lymphomas and leukemias
-Kinase from the Janus-Kinase (JAK) family -Signal Transduction and Activators of Transcription (STATs) -gene expression
____________________________________________ gets recruited and initiates phosphorylation for Cytokine receptors ? This results in signaling cascade with binding of ______________(2)________________________ ________(2)_______________ dimers travel to nucleus and regulate ________________________
Class C
a large hydrophilic extracellular agonist- binding region containing several conserved cysteine residues which could be involved in disulfide bonds
GDNF (glial derived neurotrophic factor)
a neurotrophic factor associated with Gene therapy and Parkinson's disease
BDNF (brain-derived neurotrophic factor)
a neurotrophic factor associated with Pain and neuronal disease
Risperidone
a newer antipsychotic (1994) with both D2 and 5-HT2 receptor blocking properties
D4 --- schizophrenia
- among DA receptors, clozapine possesses some selectivity for _______(1)_____ receptors implicating _____(1)______ receptor as possible site of pathology in _____________________
Dendrites
- information "receiving" elements - fine processes extending from soma in tree-like arrangement; can be many - along with soma comprises receptive field of neuron
Axon
- information "transmitting" element - a thin process extending from axon hillock (initial segment of axon as it leaves soma) along which action potential is conducted - one per neuron: can be long or short, single or branched, myelinated or not myelinated
presynaptic receptor (autoreceptors)
- receptors for the transmitter located on the neuron that releases the transmitter -the normal function of autoreceptorsis inhibitory "feedback" regulation of that neuron's firing rate and transmitter release
090
1) After RTK autophosphorylation, adaptor proteins bind and they further recruit kinases such as Ras and PI3K. 2) Kinase cascade events are triggered for both MAP kinase pathway and PI3K pathway (also called Akt pathway). 3) RTK can also activate phospholipase C for another signaling pathway. (answer = 090)
-dibenzazapine heterocycle -lipophilic --- basic -water soluble salt
-A class of neuroleptics that utilizes the tricyclic __________(1)____________ as a basic structural feature. -The __________(1)__________ is a __________________ structure with very weakly __________ properties -Piperizine substitution at the C-11 providing a center (N4') of basicity for forming ____________________ to facilitate oral dosage formulation.
Downstream Response - Long term potentiation and depression (LTP and LTD)
-AMPA receptor present --- makes synaptic connection stronger (LTP) -AMPA receptor removed --- makes synaptic connection weaker (LTD)
neuroleptic activity retains -lengthening --- shortening --- branching -keto group -maximal potency -longer duration of action
-Attachment of 3˚ amino group to the fourth carbon of butyrophenone is essential for ____________________ -Variations in the 3˚ amino group such as incorporation of nitrogen containing six membered rings (e.g. piperidine, tetrahydropyridine or piperizine) _____________ activity. -____________, ___________, or ______________ of the three-carbon propyl chain decreases neuroleptic activity -Replacement of the ______________- (e.g. with the thioketone group as in butyrothienones, with olefinic or phenoxy groups or the reduction of carbonyl group to alcohol) decreases neuroleptic activity. -Addition of p-Fluoro or similar electronegative group provides ______________________- -Replacement ofketo function with 4-fluorophenylmethane moiety such as pimozide, penfluridol and fluspirilene which posses _________________________ than original butyrophenones.
Action potential Graph
-Black = summation of Na and K - greater than both individually action potential
-Haloperidol, -Droperidol -Spiperone
-Butyrophenone derivatives drugs (3)
Long acting neuroleptics - Prodrug Design -The OH- group is converted to an ester group with an increased amount of methyl- groups is meant to increase the lipophilicity of the drug -This will cause the drug to depot in the muscle if injected, and slowly and gradually disperse throughout the body over a longer period of time *Fluphenazine enanthate n = 5 (1-2 weeks)* *Fluphenazine decanoate n = 8 (2-3 weeks)*
-Explain this mechanism of Phenothiazine heterocyclic -Explain the effect of this
NMDA glutamate receptor
-Has multiple binding sites -activation not as straight forward as GABAA or Nicotinic -Two obligatory NR1 and two NR2 of different brain region origins
-Molindone -Pimozide
-Miscellaneous "typical" antipsychotic drugs (2)
recurrent connections
-Output neurons of a circuit make connections within themselves -can have signals traveling in both directions by introducing loops in the network - powerful and can get extremely complicated
Thiothixene
-Thioxanthene derivatives drugs (1)
limbic --- basal ganglia circuitry -largely segregated
-Tissue distributions - each of the five DA receptor types exist within the ________ and ____________________ (although D1 and D2 receptors predominate). -D1 and D2 are __________________ in their cellular expression. -Functional role and importance of each type still under investigation.
feed-forward connection
-allow signals to travel one way only: from input to output
Concerted Effort at sires of drug action Steps at which drugs can alter synaptic transmission
1) Action potential in presynaptic fiber (2) Synthesis of transmitter (3) Storage (4) Metabolism (5) Release (6) Reuptake into the nerve ending or uptake into a glial cell (7) Degradation (8) Receptor for the transmitter (9) Receptor-induced increase or decrease in ionic conductance (10 )Retrograde signaling
Downstream of G protein-coupoled receptors
1) Adenylate Cyclase forms cAMP from ATP by a cyclization reaction that removes two phosphates and joins the remaining phosphate to the sugar 2) Phosphodiesterase is continually active and breaks the bond to form AMP 3) • 2 Regulatory (R) and Catalytic Subunits (C)• 4) Increase in cAMP binds R subunits, release of C subunits 5) C subunits phosphorylate cAMP response element binding protein (CREB) 6) Binds DNA sequences and transcribes downstream genes (hours to days)
Tyrosine Kinase --- phosphorylation
A _______________ is a protein that transfers phosphate groups from donor molecule, such as ATP to specific tyrosine residues in substrate proteins; this process is termed ____________________
Antihistamine
A phenothiazine heterocyclic with 2 carbon alkyl chain turns into what type of drug ?
-depolarization --- excitatory postsynaptic potential (EPSP) -increases -summate
A. Stimulation of an excitatory pathway (E1, left) generates transient ____________________ from resting membrane potential (RMP) at -60 mV called an _____________________________________. Simultaneous activation of multiple excitatory synapses (E1 + E2, middle) ___________________ the size of the depolarization, so that the threshold for action potential generation is reached Alternatively, a train of stimuli from a single input can temporally _______________ to reach the threshold (E1 + E2, right).
-GABAA -GABAC (ligand-gated ion channel) -GABAB (G protein coupled receptor)
A. y-Aminobutyric acid (GABA) 3 GABA receptor subtypes known:
-breakdown by GABA-transaminase (GABA-T) -blocksd by y-vinyl GABA
A. y-Aminobutyric acid (GABA) Catabollism :
Muscimol and THIP
A. y-Aminobutyric acid (GABA) GABAA receptor agonist :
bicuculline and picrotoxin, (both convulsants)
A. y-Aminobutyric acid (GABA) GABAA receptor antagonist:
increase in membrane permeability to Cl- --- thereby hyperpolarizing the neuronal membrane
A. y-Aminobutyric acid (GABA) Mechanism of GABAA receptor activation:
major means of inactivation
A. y-Aminobutyric acid (GABA) Reupatake :
L-glutamic acid ---(GAD)--> GABA
A. y-Aminobutyric acid (GABA) Synthesis :
44
A. γ-Aminobutryicacid (GABA) •Reuptake (GAT1) •Transport into glial cells (GAT3) •Conversion to glutamine (GS) •Transport into GABAergic neuron (SAT) •Package into vesicles (VGAT) (answer 44)
-midbrain ventral tegmental area (TVA -striatum --- cortex -motivation, normal affect, orderly thinking, "drive" states, pleasure and reward
A10 Mesolimbic DA neurons -cell bodies originate in __________________________ -axons innervate limbic portion of _________________ (nucleus accumbens )and ______________ -Dopamine (DA) release from these neurons important for __________________________________________
-substantia nigra pars compacta -axons -normal extrapyramidal motor function
A9 Mesolimbic DA neurons -cell bodies originate in ______________________ (dendrites extend into pars reticulata) -_____________ innervate corpus striatum -Dopamine (DA) release in striatum essential for ___________________
•"Nicotinic" cholinergic receptors - ligand-gated ion channels; prototype agonist is nicotine •"Muscarinic" cholinergic receptors - G protein coupled receptors (M1- M5 subtypes); prototype agonist is muscarine
Acetylcholine (ACh) 2 Receptor families:
Alzheimer's disease (death of ACh neurons originating in the nucleus basalis of Meynertand projecting to the cerebral cortex)
Acetylcholine (ACh) ACh involvement in CNS disease states:
-acetylcholinesterase ("true") - in neural tissue (in synaptic cleft) -butyrylcholinesterasee ("pseudo") - in plasma, liver
Acetylcholine (ACh) Cholinessterase enzyme divided into 2 classes :
hydrolysis by cholinesterase enzyme to yield acetate and choline
Acetylcholine (ACh) Inactivation:
vesicular storage, Ca++ dependent exocytotic release
Acetylcholine (ACh) Storage and release:
-Rate-limiting step is choline uptake (blocked by hemicholinium) •Consumption of choline or lecithin may increase brain ACh content; controversial (choline ingestion → fishy odor)
Acetylcholine (ACh) Synthesis:
88
Acetylcholine (ACh) •Degradation (AChE) •Transport into presynaptic site (CHT) •Conversion to ACh(C h AT) •Package into vesicles (VAChT) (Answer 88)
54
Acetylcholine (ACh) chart (answer 54)
12
Acetylcholine ACh Picture (answer 12)
1234
All of the super families of receptors can interact with one another (answer 1234)
dimerization
An Agonist bindig to thee outside of the Receptor Tyrosine Kinase causes ____________________
third generation antipsychotics
Apriprazole (D2 partial agonist)
No
Are coactivators part of the protein ?
atypical agents
Aripiprazole' antagonism of 5-HT2A confers the same advantages noted in _______________
-Loxapine -Clozapine -Risperidone -Quetiapine -Olanzapine -Ziprasidone -Apriprazole
Atypical second generation antipsychotic drugs (7 of them)
456
Catecholamine •Reuptake (DAT/NET) •Package into vesicles (VMAT2) (answer 456)
123
Catecholamine Dopamine chart (answer 123)
09
Catecholamine Norepinephrine chart (answer 09)
pre-synaptically --- post-synaptically
Catecholamine receptors: can exist both _________________ and ______________ at many synapses
Tyrosine
Catecholamines _______________ , a dietary amino acid, taken up into neurons by active transport
Soma
Cell body: Perikaryon -contains nucleus and most of cytoplasm -features of active secretory cell (large nucleus, lots of endoplasmic reticulum, prominent Golgi)
55
Chart about GABA (answer 55)
77
Chart about Glutamine (77)
899
Chart of side effects -(answer 899)
5432
Chart on dosages of antipsychotic drugs (answer 5432)
32
Cholinergic pathway (answer 32)
ACh breakdown --- prolonging
Cholinesterase inhibitors block ______________, thereby _________________+ ACh actions
outside --- inside
Cl- and Na+ typically move from _____________ to ______________
Organic
Classification of psychoses based on cause and symptoms: -cause is known -due to impaired cerebral tissue function -cognitive and intellectual decline -can be secondary to drug abuse, metabolic or toxic insult, trauma, infections, or structural disease of he nervous system
idiopathic
Classification of psychoses based on cause and symptoms: -cause not known, -may have a genetic component -schizophrenia denotes this form
332
Coronal view of Hormone pathways Red =GABA Green = Mesopcorticolimbic Blue =ACh (answer 332)
DA stabilizer
Current clinical practice Aripiprazole termed a "_______________r" because its high binding affinity allows it bind to and block access of DA to D2 receptors, while its partial agonist activity modestly stimulates D2receptors considered third generation antipsychotic, cariprazine (Vraylar®) belongs to the same category lower weight gain, little effect on prolactin levels, no extrapyramidal side effects
-Third Generation -lower --- prolactin --- extrapyramidal
Current clinical practice Aripiprazole -considered ___________________ antipsychotic, cariprazine (Vraylar®) belongs to the same category _____________ weight gain, little effect on ____________ levels, NO _______________ side effects
D2 receptors
Current clinical practice Aripiprazole access of DA to D2 receptors, while its partial agonist activity modestly stimulates ___________________
partial agents
Current clinical practice Aripiprazole is first antipsychotic drug with ________________ activity at D2 receptors; affinities, D2 = 5-HT2A >D4 >α1=H1 >>D1.
Apriprazole
D2 = 5-HT2A > D4 > α1 = H1 >> D1 α - alpha adrenergic, H - Histamine, 5-HT - serotonin, D - dopamine, M - muscarinic
Haloperidol
D2 >α1 >D4 >5-HT2A >D1 >H1 α - alpha adrenergic, H - Histamine, 5-HT - serotonin, D - dopamine, M - muscarinic
-D2 long -D2 short (they differ by a 29 amino acid insert in the 3rd cytoplasmic loop)
D2 can have two isoforms called ________ and ________
Clozapine
D4 =α1 >5-HT2A >D2 =D1 α - alpha adrenergic, H - Histamine, 5-HT - serotonin, D - dopamine, M - muscarinic
Negative
DSM-V criteria : Symptoms including 2 or more of the following -affective (emotional) flattening -withdrawal, depersonalization, asociality -poverty of speech and thought -anhedonia, loss of motivation
Positive
DSM-V criteria : Symptoms including 2 or more of the following -hallucinations, usually auditory (voices talking to patient) -delusions (false beliefs), grandiosity, paranoia -disorganized thinking, speech; tangential thinking, "word salad" - bizarre behavior, catatonia
-Ultra-short neurons -Intermediate length neurons -Long-length projections
Dopamine neurons 1) __________________________ •Retina and olfactory bulb neurons 2) ________________________ •Hypothalamus to pituitary (mediate endocrine functions) 3) _________________________ •Substantia nigrapars compacta (A9) neurons -project to striatum; mediate "extrapyramidal" motor functions; die in disease; may be overly active in Huntington's disease •Ventral tegmental area (A10) neurons - project to limbic areas of brain; thought to mediate pleasure and reward, excessive activity also implicated in schizophrenia
Mesopcorticolimbic
Dopamine pathways -starts from Ventral tegamentum area (VTA) and extends through the ventral striatum and into the frontal cortex
Nigrostriatal
Dopamine pathways -starts from substantia nigra that extends to the corpus striatum region
Tuberoinfundibular
Dopamine pathways starts from the hypothalamus and extends into the pituitary
787
Dopamine receptor subtype chart (answer 787)
434
Endocannabinoids - Biosynthesis 2-AG is the transmitter (answer 434)
939
Endocannabinoids - retrograde transmission called retrograde because it doesn't go forward, only backwards (answer 939)
101
Endocannabinoids chart (answer 101)
Catechol-O-methyltransferase (COMT)
Enzymatic Degredation •Extraneuronal metabolism •Places a methyl group on m-hydroxyl position of catecholamine
Monoamine oxidasse (MAO)
Enzymatic Degredation •Primarily intraneuronal, in cytoplasm of nerve terminal •Metabolizes catecholamine to the corresponding aldehyde •Blocked by a class of drugs known as MAO inhibitors
coavtivator --- dissociation
Estrogen Receptors: The binding of an agonist induces a conformational change that allows binding of a ___________________ and the __________ of chaperone proteins
-block --- psychotic symptoms -DA levels --- psychotic symptoms -# brain D2-like receptors --- up-regulation -antipsychotic drug potency -D2 receptor locus
Evidence to support Dopamine theory of Schizophrenia Drugs which ______ DA receptors (especially D2-like receptors) reduce ______________ especially positive symptoms, less so negative symptoms -Drugs which increase synaptic _________ can cause ___________________: -amphetamine (which releases brain DA), L-DOPA (which increases brain DA synthesis) -cocaine (which blocks dopamine re-uptake) can all cause paranoid psychotic symptoms similar to schizophrenia -PET scans reveal ↑ __________________________ in caudate nucleus of drug naïve (untreated) schizophrenics; suggests that D2 __________________ is a feature of disease process, not caused by chronic antipsychotic drug treatment -Strong correlation between D2-like receptor blockade and ____________________ -GWAS study 2014 shows genetic association of schizophrenia with the _______________________
-Clozapine -Olanzapine -Loxapine (X=CH3 -Amoxapine (X=H) -Quetiapine
Examples of Dibenzazapines (5)
1) Started with Meperidine (analgesic) structure, and added 2 carbons and a ring to make Propiophenone analog -Propiophenone analog is 200x more potent than Meperidine 2) From Propiophenone analog, another carbon was added to make Butyrophenone analog -Butyrophenone analog potent analgesic resembles activity of Chlorpromazine 3) Then the COOC2H5 of the Butyrophenone analog was modified to an OH group --- and a Fluorine was addd to one of the rings, which resulted in Haloperidol -Haloperidol bind with equally high affinity to D2, 5-HT2, putative a2 receptors
Explain this picture of the development of butyrophenone neuroleptics
The G protein is activating an enzyme that generates a diffusible second messenger
Explain this what is happening in this picture
The activated G protein is interacting directly to modulate an ion channel
Explain this what is happening in this picture
-IP3 --- Ca2+ -DAG --- PKC
G protein Gq activates ______________ which increases the _____ in the cell G protein Gq activates ______________ which increases the _____ in the cell
RhoGEF --- RhoA --- ROCK
G protein Gq activates ______________ which leads to ___________ and _______
Class C
GABA and Glutamine are part of what class of G protein ?
anionic --- inhibitory synapse
GABA and Glycine are linked to __________ channels (________________)
-alpha --- neighboring -hinge --- competitive antagonist -loop C -depolarization
LGIC -- Nicotinic Acetylcholine Receptor (nAChR) 1) The agonist binding site is in the extracellular domain located at the interface between _______________ subunits and ______________ subunits 2) One part of the alpha subunit binding site acts as a ___________ that closes around agonists and opens when binding ___________________ 3) The current hypothesis is that the shift in the angle of the hinge, called ______________, gets transmitted to the transmembrane domains to open the receptor gate. 4) When the channel is opened, sodium ions rapidly enter the cell, causing _______________
ligands
Ligand gated ion channels are activated by _______________
ions --- action potential --- neuronal firing
Ligand vs voltage -gated ion channel They both pass ______ across the membrane to change membrane potential that can lead to electrical events such as __________________ or _________________
22
Ligand-gated (answer 22)
GABA
Major inhibitory transmitter in BRAIN
Glycine
Major inhibitory transmitter in SPINAL CORD
543
Metabolism of Dibenzazapines 1. Oxidative N-demethylation 2. Aromatic ring hydroxylation 3. N-oxidation (at N4) 4. sulfoxidation e.g. Quetiapine 5. glucuronidation (at N5) (answer 543)
-CYP450 -bioactive -hydroxylation -pathways
Metabolism of Phenothiazines and Thioxanthenes 1) ___________ mediated 2). Example: Chlorpromazine is demethylated, sulfoxidized (inactive), hydroxylated, glucuronidated 3). ______________ metabolites 4) .Thioxanthenes: no ring _______________ 5) Several factors affect metabolic ___________
Glucuronidation
Metabolism off Haloperidol *Observe this image and understand the types of reactions that can occur to Haloperidol * -The oxidative N-dealkylation which leads to the formation of 4-(4-Chlorophenyl)-4- hydroxypiperidine (CPHP).• -The reduction of ketone group, which leads to the formation of Reduced HP.• -The reverse oxidation of Reduced HP to HP.• -The oxidative N-dealkylation of Reduced HP.• The major Phase II metabolism of HP is reported to be ____________________ product of HP.
80%
Metoclopromide D2 antagonist in CTZ, used as antiemetic Bioavailability percentage ?
25-30%
S-(-)-Sulpiride -D2 antagonist with fewer EPS (commonly used in Europe and Japan) Bioavailability percentage ?
-presynaptic neuron --- terminals -presynaptic terminals --- neural activity -applied substance ---stimulating the presynaptic neuron \ -synapse
Necessary criteria for a neurotransmitter 1. Substance must be present in _________________ and its __________ (precursors and synthetic enzymes should also be present) 2. Substance must be released from __________________ with ______________ 3. Effects of the __________________ on a target neuron (postsynaptic cell) must be same as effects of _________________________ -antagonist of the substance should also block both 4. Mechanism for the transmitter candidate's inactivation must be present in the ____________
life-threatening
S-(-)-Remoxipride -as potent as Haloperidol but with EPS and autonomic side effects -causes ___________________ aplastic anemia
sedation anti anxiety neuroleptic syndrome --- neuroleptics
Pharmacological effects and side effects of antipsychotics CNS Effects: -_______________ - tolerance develops -mild __________ effect (can be used for other disorders) -"_____________________" - common with "typical" antipsychotics; these drugs are therefore often called "_______________" - suppression of spontaneous movement; lack of initiative, disinterest in environment; flattened affect; slowness to respond to external stimuli but easily aroused; impaired vigilance; reduced aggressiveness; loss of pleasure and reward - no incoordination or slurring of speech; withdrawal response to noxious stimuli intact; ability to answer direct questions intact - patients find drugs unpleasant to take; compliance a problem
1222
Pharmacological effects and side effects of antipsychotics Chart on ratio of D2/5-HT2A (answer 1222)
neuroleptic malignant syndrome
Pharmacological effects and side effects of antipsychotics Extrapyramidal side-effects (EPS) -onset weeks, can persist for days after stopping neuroleptic; characterized by fever, unstable blood pressure, catatonia, stupor; can be fatal; treatment: stop antipsychotic drug immediately, dantrolene or bromocriptine may help
-tardive dyskinesia -irreversible -oro-facial dyskinesias -therapy -D2-likee receptor
Pharmacological effects and side effects of antipsychotics Extrapyramidal side-effects (EPS) __________________ - late-occurring" movement disorder (onset months to years) -most severe dyskinesia, often _______________ -often characterized by ______________________ such as repeated, involuntary movements of mouth, tongue, lips, jaws; sometimes also with quick choreoathetoid movements of limbs, twisting movements, muscle spasms, dystonias -no effective _______________ (although increasing antipsychotic drug dose lessens symptoms); crucial to prevent development by using lowest effective doses of antipsychotic drug -mechanism: chronic blockade of DA receptors causes increases in ____________________ numbers in striatum (chemical denervation supersensitivity?)
-Extrapyramidal side-effects (EPS) -parkinsonian syndrome -acute dystonic reactions -akathisia
Pharmacological effects and side effects of antipsychotics H. ____________________ - neurological symptoms, common with older "typical" antipsychotics, less common with clozapine, quetiapine, olanzapine, or low doses of risperidone; classified according to time of onset: 1) _________________ - onset 5-30 days; bradykinesia, rigidity, tremor, masked facies, etc.; due to blockade of DA receptors in corpus striatum, treatable with anticholinergic drugs and amantidine 2) ____________________ - onset 1-5 days; spasm of muscles of tongue, neck, face, back (may mimic seizures); treatable with anticholinergic drugs 3)_______________ - onset 5 - 6- days; motor restlessness and desire to be in constant motion; treatable by reducing dose of the antipsychotic drug
Lowering of seizure threshold
Pharmacological effects and side effects of antipsychotics J. ________________________ -contraindicated during withdrawal from alcohol or CNS depressants -use with extreme care in epileptics
Interactions with other drugs
Pharmacological effects and side effects of antipsychotics K. _____________________ 1. potentiates effects of CNS depressants, sedative/hypnotics, alcohol, antihistamines, opiates, others
-hypersensitivity -contact dermatitis -photosensitivity -pigmentation
Pharmacological effects and side effects of antipsychotics Skin reactions - esp. with phenothiazines -___________________ reactions - urticaria, itching -_______________________(among those handling the drug) -_____________________ - resembles sunburn; use of sun screens recommended abnormal skin __________________ - grey/blue patches; seen after long-term drug use
Cardiovascular
Pharmacological effects and side effects of antipsychotics ________________ effects: -hypotension -ECG changes, esp. QT or QTC segment prolongation, possible with some agents
antiadrenergic
Pharmacological effects and side effects of antipsychotics] Autonomic effects: 2)___________________ effects (α-receptor blockade) -orthostatic hypotension and reflex tachycardia -impotence, failure to ejaculate in males (esp. with thioridazine)
-Chlorpromazine -Thioridazine -Trifluoperazine -Perphenazine -Fluphenazine
Phenothiazine derivatives drugs (5)
-no evidence -correlation -transmitter systems --- brain areas
Problems with DA theory -_____________________ for increased DA cell activity or DA release, no increase in DA levels or metabolites in brain or CSF of schizophrenics -poor temporal __________________ between DA receptor block and antipsychotic effect -correlation may not imply causation: DA receptor blocking property of anti-psychotic drugs does not necessarily indicate a causative role of DA in psychosis -other __________________ (esp. serotonin and glutamate) and _____________________(esp. cortex and thalamus) are also likely involved in etiology of schizophrenia
hypofrontality
Problems with DA theory continued: - ___________(1)___________ a decreased functional activity of the prefrontal cortex, is linked todecreased DA activity in cortex; cognitive impairment and deficits in "working memory" in schizophrenics are signs of DA deficit - ↓ # of neurons in the medial thalamus is only documented anatomical difference in brains of schizophrenics; ↓ thalamocortical connections may be basis of ___________(1)_______________
blockade --- indistinguishable
Problems with DA theory continued: -___________________ of σ site (a modulatory site on NMDA receptors) by phencyclidine causes a syndrome ____________________ from schizophrenia - drugs which only weakly block DA receptors, but which potently block 5-HT2A receptors (the "atypical antipsychotics), are highly effective
CF3 > COCH3 > Cl
Rank these in order of strength on the X of the structure -- Cl, CF3, COCH3
-nuclear receptors -receptor tyrosine kinase (RTK) -Cytokine receptor -Ligand-gated ion channel receptor -G protein-coupled receptor
Receptor Superfamilies (5 of them )
metabotropic --- hormones --- growth factors
Receptor Tyrosine Kinase are a major class of ______________________ receptors and key mediators of _____________ and __________________
cancer
Receptor Tyrosine Kinase has a critical role in the development and progression of many types of ___________________
DNA --- Hormone Responsive Elements
Receptor dimers bind to specific sites on ___________ (promoter region) designated as "____________________" or HREs with palindromic sequences, (AATCCTAA [symmetrical sequence]) which bind dimeric receptors and facilitate binding of other transcription factors
Two State-Model of receptor activation
Receptors exist in two interconvertible conformations: Active * or inactive
designated D1 - D5 receptors, all are G-protein coupled
Receptors for dopamine:
two families, designated αand β, all G-protein coupled so far identified: α1A,α1B, α1D, and α2A, α2B, α2C, and β1, β2, β3
Receptors for norepinephrine:
Hinge region
Region that combines and connects the DNA binding domain (DBD) and the Ligand bind domain (LBD)
does not
Reuptake of AChper se _____________ occur (although choline is taken up by presynaptic terminal)
48%
S-(-)-Amisulpride -D2 and D3 antagonist Bioavailability percentage ?
utero --- childhood --- adolescence
Schizophrenia may begin in ________ or in ___________, but symptoms develop and first become apparent during ______________.
cross talk
Second messenger may create "________________" which is a type of interference caused by signals traveling on nearby wire pairs infringing on another pair's signal.
diffuse
Second messengers are often free to ___________ throughout the cell
specific enzyme
Second messengers are synthesized/broken down by _________________
organelles
Second messengers can be stored in ________________
amplified
Secondmessenger signals may be ____________-
657
Serotonergic pathway (answer 657)
by monoamine oxidase (MAO) then further oxidized to (5-HIAA)
Serotonin (5-hydroxytryptamine; 5-HT) •Metabolism::
889
Serotonin (5-hydroxytryptamine; 5-HT) •Reuptake (SERT) •Package into vesicles (VMAT2) (answer 889)
fast, major means of inactivation; serotonin transporter blocked by SSRI's and some tricyclic antidepresssants
Serotonin (5-hydroxytryptamine; 5-HT) •Reuptake:
similar tocatecholamines; affected by same drugs
Serotonin (5-hydroxytryptamine; 5-HT) •Storage, release :
:-Amino acid precursor, tryptophan, taken up into brain cells from plasma; dietary intake important -Tryptophan hydroxylase inhibited by p-chlorophenylalanine(depletes brain serotonin)
Serotonin (5-hydroxytryptamine; 5-HT) •Synthesis:
909
Serotonin (5-hydroxytryptamine; 5-HT) chart (answer 909)
agonist --- antagonist
Sites at which neuroactive drugs can act to disrupt neurotransmission Drug may be an _____________ or _____________ at a transmitter receptor
-re-uptake -transmitter
Sites at which neuroactive drugs can act to disrupt neurotransmission Inactivation of transmitter: 2 major means -____________ of transmitter into presynaptic terminals - enzymatic breakdown of _______
blocked --- stimulated
Sites at which neuroactive drugs can act to disrupt neurotransmission Release of transmitter by Ca++-dependent exocytosis - can be _________ or ________ by specific drugs
disrupted --- prevented
Sites at which neuroactive drugs can act to disrupt neurotransmission Storage of transmitter within vesicles of presynaptic terminals - can be ___________ or ___________ by specific drugs
-synthetic enzymes -precursors
Sites at which neuroactive drugs can act to disrupt neurotransmission Transmitter synthesis reactions - by blocking or inhibiting synthetic ________ - by modifying availability of _______
microtubules --- cholchicine
Sites at which neuroactive drugs can act to disrupt neurotransmission Transport of transmitter to nerve terminals - occurs along _____(1)______ (can be disrupted by _____(2)________, a drug which disaggregates ____(1)_____
-storage granules -reserpine -Ca+ -sympathomimetic
Storage and release of catecholamine transmitters Stored in "______________" (vesicles) •Vesicles disrupted by ______________ (transmitter leaks out, eventually depleted) •Release is ________ dependent exocytosis •Can be elicited by indirectly acting __________________ drugs, such as amphetamine and tyramine
4-6
Structural Variation and physiochemical properties Fluorobutyropheneone ---> Diarylbutylpiperidine -lipophilioc -basic (3˚ amine) -water soluble salts -long acting neuroleptics (bioreversible esters; haloperidol decanoate _________weeks)
87
Study this picture -- Know enzymes (bolded) and what causes them lead to next step (answer 87)
axo-axonix
Synaptic arrangements and hierarchal pathways Which one?
axo-dendritic (most-common)
Synaptic arrangements and hierarchal pathways Which one?
axo-somatic (most-common)
Synaptic arrangements and hierarchal pathways Which one?
dendron-dendritic
Synaptic arrangements and hierarchal pathways Which one?
somato-somatic
Synaptic arrangements and hierarchal pathways Which one?
33
Synthesis of Glutamine to GABA and their synthesis (33)
-dopamine -nigrostriatal tract -frontal cortex
The 5-HT2A receptor is thought to modulate _________________ activity It is thought that by blocking 5HT2A receptors in the___________________ EPSEs (Extrapyrimidal side effects) are reduced and blocking 5-HT2A in the ________________ reduces negative and cognitive symptoms.
asymmetry --- amine side chain
The X on the aromatic ring at C-2 is responsible for ______________ as well as for the attraction of the _____________________________
-complementary -away --- chlorine-substitiuded ring
The structural relationship between phenothiazine and dopamine are _____________ In the preferred conformation of chlorpromazine, its side chain tilts ___________ from the midline towards the _____________________
-insulin -insulin-like growth factor -nerve growth factor -platelet-derived growth factor receptors
What are some examples of Receptor Tyrosine Kinase?
1) Nigrostriatal 2) Mesopcorticolimbic 3) Tuberoinfundibular
What are the 3 dopamine pathways (sagittal plane view) --Look at Pic
second messenger
The cAMP serves as a ________________________
multiple gene mutations
The consensus view on the causation of schizophrenia is that ________________________ in several transmitter systems act together to produce a highly variable symptom complex.
-itself -substrates
The first substrate that the kinase domain phosphorylates is ________________ -After this, then additional ______________ can be phosphorylated
Phenothiazine derivative
The first used class of efficacious antipsychotic agents (Chlorpromazine - non-selective DA antagonist)
lipophilicty --- cationized
The phenothiazine heterocycle confers a high degree of _________________ on these antipsychotics which is balanced by ___________________ (at physiological pH) amine function. -*Has a Nitrogen, which allows for a small amount go hydrophilicity*
-Steroid Receptors (Estrogen, Androgen, Glucocorticoid [cortisol], Mineralcorticoid [aldoterone], Vitamin D) -Thyroid Receptors -Retinoic Acid receptors
What are the 3 main types of Nuclear receptors?
-aliphatic -piperidine -piperazine
What are the 3 subclasses of antipsychotic phenothiazine ?
-Gi -Gq -Gs -G12
What are the 4 families of G proteins ?
-EGFR , -HER2, -HER3 -HER4
What are the 4 human epidermal growth factor receptors for Pharmacological Control of Excessive Growth Factor Signaling?
-Cyclic nucleotides (cGMP, cAMP) -Membrane lipid derivatives: (IP3, DAG) -Calcium -Gas
What are the 4 types of second messengers ?
-Phenothiazine derivatives -Thioxanthene derivatives -Butyrophenone derivatives -Miscellaneous "typical" antipsychotic drugs
What are the 4 typical antipsychotic drug classes ?
lipophilic ligands (because they can travel easily through the membrane --- hydrophilic ligands cannot, so they are not good ligands for this receptor)
What are the best types of ligands for Nuclear receptors?
Cognitive
impaired attention, deficits in learning and memory
Estrogen receptor < CB1 receptor < Insulin receptor = Nicotinic receptor
What are the sizes of Estrogen, insulin, nicotinic, and CB1 receptors in order of smallest to biggest?
Phosphatases and Phosphodiesterase
What are the two inhibitory mechanism of G protein-coupoled receptors ?
glucose homeostasis
What does insulin regulate ?
11
Voltage gated Sodium channel & Calcium Channels (answer 11)
electrical membrane potential
Voltage gated ion channels are actives by changed in _________________________
-Trophic hormones (thyroid-stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH)) -Peptide hormone (insulin, atrial natiuretiuc peptide (ANP)) -Growth factors (GF, PGDF, TGFb
What 3 things target Receptor Tyrosine Kinase
-Tumor Necrosis Factor (TNFå) receptors -Interleukin-6 Receptor (IL-6) receptor
What are 2 receptors included in cytokine receptors?
-Growth hormone -Erythropoetin -interferons
What are 3 ligands that bind to Cytokine receptors
-Enzalutamide (prostate cancer) -Tamoxifen (breast cancer) -Lipaglyn (type II diabetes) -Cortisone (anti-itch / pain relief)
What are 4 drugs that utilize Nuclear Receptors ?
-acetylcholine -serotonin -GABA -glutamate
What are 4 natural ligands ?
Atypical antipsychotic drugs
blockade at 5-HT2A receptors > D2 receptors
Typical antipsychotic drugs
blockade at D2 receptors > 5-HT2A receptors; antipsychotic potency correlates strongly with D2 receptor blockade
neurochemical (nature) ---- environmental factors (nurture)
both _________________ and __________________ factors are likely to contribute to the development of Schizophrenia.
Dopamine theory of Schizophrenia
cause is postulated to be excessive DA transmission, especially within the limbic striatum and limbic cortical areas innervated by A10 DA neurons (mesolimbic and mesocortical DA pathways)
The SNARE complex
consists of a bundle of four α-helixes, one each from synaptobrevinand syntaxinand two from SNAP-25. The structure shown here is for the docked vesicle prior to fusion. The actual structure of the transmembrane domains has not been determined and is drawn here along with the vesicle and plasma membranes for illustrative purposes
Myelin Sheath
insulates the projections of neurons and increases conductivities.
Blood Brain Barrier (BBB)
functions as a border that prevents solutes in the circulating blood from non-selectively to avoid toxic substance coming in
neuron
fundamental units of the nervous system for transforming and relaying the electrical signal
tardive dyskinesia
haloperidol is a potent neuroleptic associated with high incidence of ________________ *Haloperidol-induced dyskinesia may involve neurotoxicological mechanism similar to the dopaminergic toxicant MPTP*
