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Medchem exam 2

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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)

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)

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