Lecture 6 - Week 3 - Monday - 1-30-2017 : Medicinal Chemistry of Antihistamines - Dr. Lee
Classical physiological roles of histamine
(A) When relelased by mast cells, a major mediator of inflammation (B) Also released in the gut by (ECL) it then acts on parietal cells to increase gastric acid secretion (C) A neurotransmitter both in the central and peripheral nervous system
Both of these structures retain imidazole ring
1) Histamine 2) H2 Receptor Antagonists
Side effects of first-generation antihistamines
1) Nausea and vomitting 2) Sedation
Review: structural featuers of 1st generation anti-histamine
1) Nitrogen atom: very pivotal (you won't have the significant antihistaminic activity if replaced with another atom) 2) Two aromatic rigns attached to a cetnral atom X - which can be anything 3) 2-3 carbons as linker moleculue between x and the N groups.
Piperoxane Structure
1) Tertiary amine 2) Linker molecule 3) Oxane group: 2 oxygens 4) This molecule led to discovery of First generation antihistamines.
Important: First Generation Anti-histamines: what do they have in common
1) Tertiary amine 2) Linker molecule of 2-3 Carbons 3) Two aromatic Rings
Structural features of first-generation anti-histamine
2 Aromatic groups linked through a short chain to a tertiary amine
What is an antihistamine?
A compound that reduces or eliminates histamine-mediated effects by blocking the binding of histamine to its receptors (H1R or H2R)
Significantly less CNS-depressant effects with this first-generation antihistamine
Alkylamine
The most extensively used antihistamines until the arrival of the second-generation drugs
Alkylamine
Suitable for once-a-day dosing due to longer half-lives (up to 1 day)
Alkylamines (first-generatino anti-histmaine)
Long duration of antihistamine activity with fewer sedative and GI adverse effects compared to other first generation drugs
Alkylamines (that's why Karboski recommends them)
Image showing storage of histamine in mast cells
At phsyioglcial ph this the SOOOH group is negativiely charged because it is acidic. Will interact with the basic portion of histamine.
Used in the treatment of parkinsonism
Benadryl (Ethanolamine) - because of it is signiciant anti-cholinergic effects
Used as OTC sleep aids such as Tylenol PM
Benadryl (Ethanolamine) - because of its high sedative effects
Observation of serotonin reuptake inhibition by ____________________ led to finding of antidepressants with similar structures, such as _______
Benadryl (first-generation antihistamine) ; prozac
Storage of Histamine in basophils (he didn't really discuss though); histamine is stored as a complex with ________________
Chondroitin sulfate
How would you recognize the structure of a piperazine, a first generation antihistamine
Contains 6 memmbered ring with 2 nitgoen atoms in it.
Very important: _______________ in third membrane of histamine H1 receptor plays a critical in recognition of protonated aliphatic amine of histamine
D107 (Apartic acid in the 107th position), since it is acidic, it will be in its anion form and can interact with the protonated amine of histamine
FYI: Enterochromoffin-like cells are located where
E-cells release histamine. That works on the H2 receptors in the parietal cells in gastic gland of the gut mucosa to finally produce gastric acid.
Antihistamines are those that only bind to H1 Receptors (T or F)
F. Bind to any histamine receptor (H1, H2, H3 and H4)
Second generation anti-histamines are the H2R Antagonists (T or F)
F. Both First and Second Generation Anti-histamines are H1R antagonists but the second generation ones are bulkier and more hydrophililc. Hence they can't cross the BBB and have sedative effects.
First generation antihistmaines are H1R specific only. They don't bind to other types of receptors (T or F)
F. Not H1 receptor specific: can bind cholinergic (M) and adrenoreceptors
Imp. He kept repeating. Proton Pump inhibitors are antihistamines (T or F)
F. Proton pump inhibitors are not antihistamines. They bind to and stop the action of H+/K+ ATPase *NOT* histamine receptors.
Mast cell stabilizer are antihistamines (T or F)
F. They prevent histamine release but they don't bind to histamine receptors.
We can use first generation anti-histamines to treat ulcers (T o F).
F. We can't use first or second generatino anthistamines. We have to use H2 receptor antagonists.
Structural features: 2 Aromatic groups linked through a short chain to a tertiary amine
First-generation antihistamines. (need to remember that - on exam shows us difeerent strucutres and need to know which one is the odd one)
FYI: Is hystamine synthetsized in smooth ER, rought ER, or Golgi of mast cells and basophils?
Golgi apparatus because it is hydrophilic.
This histamine receptor is involved in allergic responses
H1 Receptor
Its X-ray structure now available
H1 Receptor of Histamine
Which histamine receptor is present throughout the body?
H1 Receptors. Smooth muscle of bronchi, gut, and uterus, endothelium and CNS.
This histamine receptor is mostly found in gastric parietal cells
H2
Histamine receptor that has minor role in allergic inflammatory process
H2 receptors (notice the word minor; more like negligible, he didn't emphasize it)
Where does histamine bind to H2 receptors?
H2 receptors in parietal cells in the gut to stimulate gastric acid secretion.
Histamine receptor that regulates the release of other neurotransmitters
H3 receptor
Where does histamine bind to H3 receptors?
H3 receptors on neurons in the CNS and PNS.
Histamine raceptor that plays a role in chemotaxis
H4 receptor
Location of H4 receptors
Hematopoeitic system.
A signaling molecule involved in local immune response, and is also a neurotransmitter
Histamine
What is this called π with regards to histamine tautemers
Histamine pros ('near', abbreviated π) tautomer. (because the NH group is nearer to the primary amine)
H1 receptor. What does H refer to?
Histamine.
Histamine and Histidine; which converts into the other
Histidine (an amino acid) is converted to histamine through histidine decarboxylase.
Histamine is synthesized by _______________ and is inactivated by
Histidine decarboxylase (in one step so pretty simple); 2 enzymes: histamine-N-methyltransferase and diamine oxidase (FYI: note how histamine is a diamine)
Cetirizine is first/second generation antihistmaine metabolite of ________________________- which is a first/second dengeration antihistamine. How are they structurally different?
Hydroxyzine; first-generation. The only difference between them is the prescence of carboxylic acid moeity.
Three possible strategies to stop the action of histamine.
I. inhibiting histamine biosynthesis; 2. inhibiting histamine release (like mast cell staiblizers) 3. blocking the histamine receptors
Remember structure of histamine
Imidazole group + Ethylene linker molecule + An amine group that is + charged at physiological pH
Histamine biosynthesis from histidine invovles _______________ followed by __________
Involves imine formation followed by loss of carbon dioxide
Is histamine an acidic or basic molecule?
It is amphoteric: can act as both acid and base depending on the pH it exists in.
Since histamine is structurally similar to other neurotransmitters, what is the pharmacological implication of that?
It makes it difficult to make antihistamines that are purely H1 receptor antagonists to treat allergies for instance. Most antihistamines exhibit blocking effects on cholinergic and adrenergic receptors as well.
Histamine is synthesized in the Golgi apparatus of mast cells and basophils (white blood cells) catalyzed by
L-histidine decarboxylase
Location of H3 receptors
Mainly in CNS
Major role of H1 Receptor
Major role in allergic response. Activation results in vasodilation, *bronchoconstriction*, and separation of endothelial cells
What is Cromolyn Sodium (MOA)
Mast Cell Stabilizer (inhibit histamine release)
What is Khellin (MOA)
Mast Cell Stabilizer (inhibit histamine release)
What is Nedocromil Sodium (MOA)
Mast Cell Stabilizer (inhibit histamine release)
Second Generation Anti-histamines are more/less hydrophilic and more/less bulky than First generation antihistamines
More (that's why can't cross BBB); More bulky (another reason why they can't cross the BBB) - Notice the carboxylic acid moeity in Patanol.
The more electron-rich, the less/more basic the molelcule .
More basic - the ethylamine group in histamine is more basic because the elelctron pair in imdiaiozle is delcoalized over the ring so it is like there is "less electrons on that nitrogen atom comapred to the ntirgoen in ethylamine"
At physiological pH, histamine exists in mono/di- protonated state?
Mostly mono- (96%), di- (3%), and non-protonated (<1%) species
Image showing structures of different alkylamines
Notice an aromatic ring and a pyridine ring; aromatic ring may be subsituted with a halogen, spacer molecule linked to an amine like other first generation antihistmaines.
Showed anticholinergic effects as well, which has been annoying side effects of almost all the antihistamines introduced over the next several decades
Piperoxan
The first antihistamine
Piperoxan - reduced histamine-induced bronchospasm in guinea pigs
This molecule led to discovery of First generation antihistamines.
Piperoxane
Physiological role of H2 receptors
Regulates gastric acid secretion;
Shitty flash card - ignore
Shitty flash card - ignore
Antihistamines is the same thing as histamine receptor antagonists. (T or F)
T.
Mast cell stabilizers are NOT antihistamines (T or F)
T. Do not have intrinsic anti-histaminic activity because they don't associate with histamine receptors.
Review: histamine's physiological actions will be mediated by its receptors (T or F)
T. For instance when it binds to H1 receptors, it will lead to bronchoconstriciton. When bound to H2 receptors, it stimulates gastric acid secretion.
All of the histamine receptors are G-protein coupled receptors (T or F)
T. Histamine is hydrophilic molecule. Makes sense that recpetor has to be transmembrane and hydrophilic too
Histamine and Acetylcholine are structurally similar (T or F)
T. In fact, histamine is structurally similar to 3 other molecules. They all contain a + charged amine bouned to a central molecule by a 2 Carbon linker molecule. (+ charge is not shown for three molecules here but in physiological pH they are protonated)
There are significant structural differences between the structures of First Generation vs. Second Generation Anti-histamines (T or F)
T. Note the differences
H1 receptor antagonists are antihistamines (T or F)
T. They bind to and stop the action of histamine receptors.
Histamine can act as a neurotransmitter (T or F)
T. When released by neurons to act on neighboring neurons.
What is this called τ with regards to histamine tautemers
Tele ('far', abbreviated τ) tautomer (because the NH group is farther away from the primary amine)
Which conformation isomer of histamine is more likely to interact with histamine receptors: the anti or the gauche
The anti is favored for interactions with H1 and H2 receptors
Of the two basic centers of histmaine, which moeity is more basic?
The ethylamine because in imidazole, nitrogen is in aromatici rign so its lone pair is delocalized all over the ring and isn't readily available to accept a proton. (not that basic)
So at physiological pH, histamine will be protonated on which one of its basic centers.
The ethylamine because it is the more basic center.
Review: which tautmer and which conformation isomer of histamine is favored?
The tele (τ or far) isomer and the anti confomrational isomer.
In aeuqous solution, which histamine tautomer is more predominant.
The tele tautomer is more existant (he said it is because it can form more intermolecular hydogen bonding)
Give an example of a drug to recommend that inhibits histamine biosynthesis
There is no drugs on the market that inhibit histamine biosynthesis
FYI: how do you think H1 Receptor Antagonists (first generation anti-histamines) cause nausea and vomitting
They cross the BBB probably mess with the chemoreceptor trigger zone which messes with the vomitting center in the brain.
most effective antihistamine on the market
Who knows?
What are the two structural centers of histamine
alkylamine (an ethylamine group) and imidazole
H1 receptor antagonists treat
allergic disorders
Histamine's action is mediated by
by the activation of histamine receptors H1, H2, H3, and H4, all of them G protein-coupled receptor (GPCR)
These are drugs that countered the effects of histamine. They are lipophilic molecules that could penetrate the CNS and cross the BBB
first generation H1 antihistamines
H2 receptor antagonists treat
gastric hypersecretory disorders
Histamine stimulates gastric acid secretion when bound to __________ receptor.
h2. That's why first/second generation antihistamines don't work because they bind to H1R.
In the CNS, which enzyme: diamine oxidase or histamine-N-methyltransferase is responsible for histamine degradation after its release into the synapse.
histamine-N-methyltransferase - Important enzyme.
Agents that stabilize mast cells do so by
inhibiting their degranulation
For stability, histamine has to be stored in granules and be in complex with other molecules or else
it is (the unstored histamine) rapidly inactivated by enzymes, histamine-N-methyltransferase or diamine oxidase. The The methyltransferase enzyme adds a methly l group on the imidazole ring that it can't act as an agonist to the h receptors anymore.
A plant used by ancient Egyptians for spasmolytic activity
khellin, a mast cell stabilizer that has bronchodilatory effects since it prevents the release of histamine
Inhibitors of histamine relelase are the
mast cell stabilizers
Cells that release histamine
mast cells, enterochromaffin-like cells, and neurons
H1 Receptors show 40% homology with
muscarinic (cholinergic) M1 receptor - this explains why first generation antihistmaines have anti-cholinergic effects
H2 histamine receptors are mostly found in _____________ cells of the stomach
parietal
In order for the enzyme histidine decarboxylase to convert histidine into an active histamine molecule it needs
pyridoxal phosphate cofactor.
Storage of Histamine in mast cells: In mast cells, histamine is stored in ______________________ forming a complex with ______________ residues of ________________
secretory granules; acidic; proteoglycan heparin
Tautomers:
structural isomers that differ in location of a proton and a double bond - histamine has two tautomers
Aspartic acid moeity in H1 receptors binds with
the protonated aliphatic amine in the histamine molecule.
Which histamine tautomer will be the one that is most likely to interact with histamine receptors:
the tele receptor because it is the one that is more existant in aqueous solutions.
