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Lecture Seventeen

Histamine Receptor Targets

QuestionAnswer
"Madness was reported first in the Middle Ages e.g. insomnia, psychomotor agitation, vivid hallucination, joint pain, spasms, convulsions and spontaneous abortion. What was the cause of all this madness? ergot contamination of food source e.g. in the flour in bread. (so when they went to monastry to get cured they were not cured because of the monastry but because of having a dif. food source there but they didnt realise this.
Henry Dale studied ergot alkaloids and identified two mysterious compounds that were consistently present. What were they? Alkaloid one, now called Acetylcholine and Alkaloid two, now called Histamine.
Where are histamine neurons localised to? The Hypothalamus
Among other things, Histamine contributes towards CNS modulation of wakefulness and metabolism. What drug previously learnt does this relate to? Clozapine which has side effects of sedation and weight gain. So the drug must be an antagonist for histamine receptors.
Among other things, Histamine contributes towards CNS modulation of wakefulness, metabolism and cognition and attention. What drug previously learnt does this relate to? TCAs (Tricyclic AntiDepressants) which cause drowsiness, sedation, weight gain, memory impairments. So this drug must also be an antagonist for Histamine.
Describe the synthesis of Histamine Histamine is synthesised from histidine to histamine with histidine decarboxylase as the enzyme that helps.
Too much histamine is not good for you! What happens? Nausea, vomiting, flushing, sweating, delirium and headaches.
What is the prototype drug of the first generation H1 receptor antagonist called? What is it's mechanism of action? What are it's side effects? Benadryl, H1 receptor antagonist. GI problems and CNS depression (drowsiness, psychomotor slowing)
What is the prototype drug of the second generation H1 receptor antagonist called? What is it's mechanism of action? What is key about it's distribution? Claritin, H1 receptor antagonist, it has wide distribution but it does not cross the BBB
As pharmacologists, what could we target in the emetic pathway to prevent or fix motion-related vomiting? H1 receptor antagonist (e.g. drug called Dramamine) or mAChR antagonist
What happened in 2000 relating to history of Histamine? Much more interest in pharmaceutical potential of H3 receptor compounds
Describe the H3 receptor subtype Identified in 1987. Is Gi-protein coupled and has high localization in the CNS (presynaptic) with minimal to none in periphery. Since it only acts in brain and not the periphery it has less side effects.
What two things are unique about the H3 receptor? 1) H3 is a pre-synaptic receptor which modulates release of histamine AND other neurotransmitters. 2) H3 is constitutively active - always turned on even if there is no histamine in its site.
So H3 receptors have high constitutive activity. This has implications for designing ligands, how so? You need an H3 receptor INVERSE agonist to turn it off and this increases wakefulness, suppress appetite and improves learning.
Targeting H3 has potential for sleep drugs. In animals models H3 receptor _______s promote drowsiness and slow wave sleep. What is a potential pharmacotherapeutic application of this? Could be used as a hypnotic (sleep drug) and maybe replace current insomnia drugs.
Targeting H3 has potential for sleep drugs. H3 receptor _________ ________ promote wakefulness. What is a potential pharmacotherapeutic application of this? Could be used for Narcolepsy hypersomnia or for a Cognitive enhancer to make you more productive
Targeting H3 also has potential for obesity drugs. In animal models, H3 receptor ________ ________ decrease overall food consumption. What is a potential pharmacotherapeutic application of this? Could be used for an anti-obesity agent, diet pills.
Targeting H3 also has potential for cognition drugs. In animal models H3 receptor inverse agonists have mixed results but could have potential application for? ADHD, AD (Alzheimers Disorder), Schizo for cognitive symptoms, or as a CE.
Designing a good H3 receptor drug: Pre-Clinical Research involves what steps, specific to designing a good H3 receptor drug? What does each step determine? 1) Find chemicals that bind the H3 receptor subtype (determines selectivity). 2) Determine which ones exhibit inverse agonism (determines efficacy). Determine which ones bind the best (determines affinity).
Pre-Clinical Testing involves what steps? And what does each step determine? 1) Test candidate drugs in animals to determine toxicity and pharmacokinetics 2) Test candidate drugs in animal models to determine effectiveness
What is one of the biggest challenges in drug design of psychoactive drugs? The drug must get into the brain!
One way to get a drug into the brain is via Cranial delivery (open up skull and inject it into brain). What is the pro of this and what are the cons? Pro: ensured deposition in the brain. Cons:very limited parenchymal (brain tissue) distribution as you only really get distribution near tip of syringe. And crantiotomy - you have to open you skull
Another way to get a drug into the brain is via Vascular Delivery (IV, SC, IM). What are the pros of this and the cons? Pros: widespread parenchymal distribution possible, much preferred ROA. Cons: Somatic (=body) distributing possible - so mat distribute to every tissue of the body, and crossing of the BBB!
With psychoactive drugs, to cross the BBB they must be.... small molecules with high lipid solubility and must cross the BBB in pharmacologically significant amounts
What are the 3 ways to tackle BBB permeability (get it to cross the BBB)? 1) Chemical approaches - retrofit your candidate so it is more lipophilic. 2) Biological approaches - exploit endogenous machinery, +/- retrofitting. 3) Use a Trojan Horse- sneak in.
Can we use antihistamines to treat the common cold? Yes, they help you go to sleep and sleep/rest is one of the best things to help get over a common cold!
Created by: alice476