Binding affinity question

dirzted

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Ok all my pharmacology research basically comes from wikipedia and nothing else so excuse me if this is a completely stupid question but I keep reading up on the specific binding affinity of certain drugs on different receptors and was wondering what concentration of a substance at a receptor site makes it become potent? (smaller amount, greater physiological response) Like if something greatly changes the state of a person at 100nm concentration at a specific receptor, does that make it potent? Obvi there's more than one receptor involved in the process of drug eliciting a response, but like in the case of opiates you could say the mu receptor is the most important receptor involved in the mechanism of action of the opiate, so are the concentrations and resulting physiological response relative to how powerful the opiate is? Like hydrocodone is less potent than morphine, so 300nm (amounts are totally made up) of the hydrocodone metabolite is needed to bind to the receptor where as only 100nm of morphine was needed to bind to elicit the same response.

I'm sure this question demonstrates my lack of understanding of a lot of these terms so I hope some of you can educate me a little more on how binding affinity works or just on pharmacology in general
I hope this question even makes sense at all haha
 

Hammilton

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Your question is kind of all over the map, requiring a dozen explanations of a dozen complicated issues.

Hydrocodone is equipotent to more potent than morphine, actually. Certainly through the oral route.

These numbers are usually in nm/L (nanomoles per litre of fluid). Ki values are a measure of how much of a given drug is required to displace another ligand from the receptor. A chemical with higher affinity will displace the ligand at lower concentration than a weaker one.

Additionally, you'll often see EC50 values given. That's a measure of the concentration needed to elicit a 50% of the maximum response in the receptor. This is important to note because a compound may have very high affinity but weak efficacy. Efficacy is almost always compared to the endogenous ligand, which is why you'll see some compounds having >100% efficacy. You'd need to look at this to determine if the drug is an agonist. Antagonists are usually measured by IC50.

Whether a Ki value of 100nm/L at a given receptor is potent or not is a subjective thing- determined, usually, by comparing it to other compounds that bind to the same receptor.

Like if something greatly changes the state of a person at 100nm concentration at a specific receptor, does that make it potent? Obvi[sic] there's more than one receptor involved in the process of drug eliciting a response,
That's not how this is done. The potency is determined by tests conducted in vitro- not by administering it to a person. I mean, yeah, you could administer it to a person to determine what a good dose would be, and thus what sort of blood concentration this gives you, but it'd be a mostly valueless endeavor. They're looking at the concentration of the solution they're using.

Studies are done looking at dose-response or dose-effect curves in animals, but that's not what we're talking about here.


You're also mixing up in vitro and in vivo studies. The binding numbers you read are all conducted in vitro. But then you're talking about the effects produced in a person. There are so many different things that can effect how potent a compound is when it's actually administered to a human that it's hard to list them here. How quickly it's absorbed, how rapidly it's metabolized, it's ability to penetrate the blood brain barrier, the degree to which it's plasma-bound, distribution, etc etc. None of these things are considered when you're looking at a Ki value. Buprenorphine may be much more potent than morphine, for instance, but if you're swallowing it instead of consuming it sublingually, you wouldn't believe that to be true. Not to mention the fact that it's also a partial agonist (ie, it has weak efficacy at the receptor).

With psychedelics it becomes even more complicated. These you have to consider the downstream events that a compound effects. A compound may have high affinity for 5HT2A, as an agonist, no less, because it's binding doesn't stimulate PLC or PLA2 properly for psychedelic effects.

If you can come up with a question that focuses in a little more on a specific area of binding I'll be more than happy to help, but this is a complicated issue and writing an overview of it in a few paragraphs isn't effective.
 

Cortexiphan

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A good real life example here is LSD, which is incredibly potent in vivo, but when compared to other 5-HT2A agonists in vitro it does not stand out in terms of affinity or efficacy. There are dozens of compounds that are more potent than LSD in vitro.
 

dirzted

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Ya okay thats what I kinda thought haha well thanks a ton anyway that still gets me alot closer to understanding the concept as a whole.
 

Solipsis

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If you can come up with a question that focuses in a little more on a specific area of binding I'll be more than happy to help, but this is a complicated issue and writing an overview of it in a few paragraphs isn't effective.
I'd say this overview has a pretty good affinity, but the efficacy may be limited by comparison..
 
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