Posted by Adam on January 20, 2000, at 18:33:18
In reply to Re: what the heck is a partial agonist?, posted by michael on January 20, 2000, at 16:16:47
> > My understanding is that a partial agonist is a drug that activates a receptor to less than the maximum extent. I don't know how to express this quantitatively, though. (Where's Adam when we need him! :-) I think that the partial agonists can behave as antagonists at high concentrations.
> >
> > Buspar is a partial agonist at 5-HT1a receptors and, I believe, a full antagonist at D2 receptors.
>
> Could someone rephrase the last sentance above, without using the words agonins & antagonist? What's the net effect on the serotonin & dopamine levels/availability?
>
> michaelFirst, it's difficult for me to discuss this without using terms like "agonist" and "antagonist" so I'll try to define those terms:
Agonist: A substance that binds/has affinity for a receptor (such as the serotonin 1A or "5-HT1A" receptor) that stimulates a response mediated by that receptor. It might just mimic the action of the natural ligand (i. e. serotonin binding its receptor) or have other effects not caused by the natural ligand (like LSD binding the serotonin receptor, perhaps?)
Antagonist: Essentially the opposite of the agonist. It binds/has affinity for the receptor and blocks responses mediated by that receptor. A dopamine D1 antagonist, for instance, would bind the D1 receptor and prevent or inhibit neurotransmission mediated by this receptor via binding of the natural ligand (dopamine). The ability of such a substance to antagonise such signalling is related to its binding affinity, i. e. its kinetics of binding must be more favorable than the agonist (be it the natural ligand or maybe a drug) to block signalling.
(There are so-called "indirect" agonists and antagonists, but we won't go there.)
My understanding of buspirone's behavior at the 5-HT1A receptor is as follows: It is a presynaptic 5-HT1A ("somatodendritic autoreceptors") full agonist and a partial agonist at postsynaptic 5-HT1A receptors. It was once thought that buspirone just looked like a "partial" agonist at postsynaptic receptors because there was a large reserve of the presynaptic autoreceptors (need for constant sensitivity despite receptor turnover following ligand binding, perhaps), while such was not the case for the postsynaptic cells. This would make the presynaptic-receptor-mediated response appear more sensitive, at least initially, before presynaptic desensitization takes place. However, later on, postsynaptic 5-HT1A full agonists were synthesized, so there goes that theory, apparently. (I can't find the paper now that proposed this, darnit, but I'll look). Thing is, I haven't heard of any other explanation for this behavior, and can't for the life of me understand why the same receptor on one cell (mere micrometers away from another cell, to boot) would have different binding affinities. I could propose all kinds of possible explanations (minor stearic inhibition of buspirone binding due to receptor cofactors found only on postynaptic cells, differential post-translational processing, alternative splicing of 5-HT1A messenger RNA (though this would be an obvious and easy thing to check out, and there's nothing in the literature)), but I'd be pulling things out of my butt, essentially.
To be honest, I really don't know what causes the difference, and I'm not aware of any definitive research on the question.
poster:Adam
thread:19073
URL: http://www.dr-bob.org/babble/20000112/msgs/19286.html