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Im a little confused on how efficacy affects a drugs potency

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purplehaze147

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Aug 19, 2010
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I'm having trouble on figuring out how efficacy effects a liglands potency. I know the basics I think. A super agonist has a higher efficacy then the relative endogenic neurotransmitter(naturally occurring ligland in the brain or body), a full agonist has about the same efficacy as the relative endogenic neurotransmitter, a partial agonist has a lower efficacy then the endogenic neurotransmitter, a silent agonist is a partial agonist with a efficacy so low it acts as a anatagonist, and an inverse agonists efficacy is so low it occupies every receptor site of the relative endogenic neurotransmitters receptors, a inverse agonist would be a true antagonist. Right?

But Im still not sure how it effects a drugs potency, the efficacy of potent drugs varys a lot. I understand how affinity effects the potency tho, the higher the affinity the more tightly the ligland binds to the receptor and I realize that efficacy also comes into play when determining a drugs potency.

Can someone please explain.
 
Affinity can be largely ignored; EC50/peak efficacy and absorbtion are the two main factors that determine a drug's "potency". For instance, you can have high-potency ligands like CB25 or loperamide that, because they aren't effectively delivered to the brain, won't produce an effect.
 
Drug concentration and receptor densities are also going to be a factor. If you have a low receptor density a particular concentration, you will have a greater effect than with a higher receptor density at the same concentration. I don't think you can ignore affinity - it is a large determinant of potency. This is because a drug with higher affinity is more likely to bind to the receptor.

EC50 is just a point on the dose-response curve. It doesn't 'determine' anything - we calculate it mathematically based on the response.

Inverse agonists are tricky. They can have just the same potency as a normal agonist though, they just produce an effect that is the OPPOSITE to what we usually see. Whether a drug is an agonist, inverse agonist or antagonist does not correlate to potency. Antagonist, again, can have high potency. They don't produce an effect - They BLOCK other agonists (endogenous or otherwise) from binding and producing an effect.

Hope that helps :)
 
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What about burenorphine and 25i-nbome, they have low efficacy but they're very potent. I understand but I kinda don't lol its a lil confusing.
 
I think that you might be confusing affinity (or possibly intrinsic activity) with efficacy. I'll try to explain :)

Efficacy is a measure of how 'well' a drug works. For example, you're in a pharmacy and you want something to ease your headache. You could choose paracetamol or a herbal remedy. The paracetamol is probably going to be more efficacious, i.e. it works better to cure your headache. Efficacy is determined by things like clinical trials, to make sure drugs actually do what the drug company says it will. So based on this, we know that both buprenorphine and 25i are efficacious (they both get you high).

However, when it comes to affinity and potency, buprenorphine and 25i are actually very different.

Buprenorphine has very high affinity for the mu opioid receptor, but has low intrinsic activity. It is a partial agonist, which means the maximum effect is LOWER than that of a full agonist. This is often a good thing, as it is much harder to overdose on drugs like these. Basically, after a certain point, increasing the dose of buprenorphine will NOT give you a greater effect (it can however mean increased withdrawal symptoms).

25i-NBOMe is a full agonist with high affinity for the 5HT-2A receptor. It binds to receptors easily. Because it is a full agonist, you will also find that increasing the dose DOES mean you get an increased effect - the 'ceiling' isn't there like it is with buprenorphine. That's why you'll hear about people easily overdosing on 25i.
 
Ok I understand, thanks. Idk y I thought 25i was a partial I must of misread potent or confused it with another drug.
 
It should be noted that strong partial agonists can have many of the same dangers as full agonists, esp in overdose. Take DOB and DOM for example. Both compounds are potent 5ht2a partial agonists, but you sure as fuck wouldn't want to OD on them! Actually, non-weak partial agonists can have many of the same dangers that full agonists have in higher doses. For example, flurazepam is a benzodiazepine partial agonist, but with the exception of supposedly producing tolerance less quickly, it has exactly the same dangers as a full benzo like clonazepam or diazepam. You should always do your research on compounds you are planning on ingesting, know the dangers and the limits! Generalizations can kill...

Oh, one other interesting thing to note. There are such things as superagonists and covalent agonists. They are quite rare but very interesting nonetheless. A superagonist is a drug with greater than 100% efficacy at its target, ie it is more effective than the natural ligand. The most infamous example of a superagonist is the CD28 (T cell receptor) superagonist TGN1412, which caused extremely toxic reactions and organ failure in all volunteers in a clinical trial by triggering a powerful immune response. Other examples of superagonists include the very strong opioids like carfentanyl and etorphine. Covalent agonists are interesting because they permanently bind to receptors. There are a few opioid covalent agonists, but AFAIK they haven't been tested in humans because of the obvious dangers.
 
ebola? said:
I thought that the psychedelic amphetamines were full agonists. This is at least the case with DOI. . .

ebola
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DOI is indeed a full agonist. From what I've read, DOM, DOC, DOB, and DOET are all very strong partial agonists with high binding affinity. Something like 80%+ activity.
 
ebola? said:
Ah. Okay. I think the cut-off point for "full agonist" just varies, depending on researcher and assay method.

ebola
Click to expand...

I believe that has something to do with how accurately they are measuring efficacy. I have read older articles where they say that some full agonists could also be strong partial agonists with activity over about 85%, and vise versa, because (at the time, anyway I suppose) it was impossible to distinguish between a very strong partial agonist and a true full agonist. I am guessing that older studies may have identified the various strong partial agonist members of the DOX family as full agonists because, as far as they were able to measure, it was the truth. Its fascinating how certain accepted conclusions are revised as the precision of instrumentation advances...
 
SeenSoFar said:
I believe that has something to do with how accurately they are measuring efficacy. I have read older articles where they say that some full agonists could also be strong partial agonists with activity over about 85%, and vise versa, because (at the time, anyway I suppose) it was impossible to distinguish between a very strong partial agonist and a true full agonist. I am guessing that older studies may have identified the various strong partial agonist members of the DOX family as full agonists because, as far as they were able to measure, it was the truth. Its fascinating how certain accepted conclusions are revised as the precision of instrumentation advances...
Click to expand...

It's true that variability accounts for some of that confusion, but it also depends on how you answer "efficacy at what?". Using opiates as an example, you could rank different drugs based on their efficacy as analgesics, then rank them based on their efficacy at inhibiting adenylyl cyclase activity and get very different answers.

For psychedelics it gets even more complex because they can be full agonists at activating one pathway downstream of 5-HT2A, but partial agonists at others. See:http://www.bluelight.ru/vb/threads/620862-5-HT2a-Highest-Efficacy-Agonists
 
endotropic said:
It's true that variability accounts for some of that confusion, but it also depends on how you answer "efficacy at what?". Using opiates as an example, you could rank different drugs based on their efficacy as analgesics, then rank them based on their efficacy at inhibiting adenylyl cyclase activity and get very different answers.

For psychedelics it gets even more complex because they can be full agonists at activating one pathway downstream of 5-HT2A, but partial agonists at others. See:http://www.bluelight.ru/vb/threads/620862-5-HT2a-Highest-Efficacy-Agonists
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Right, the line between partial agonists and full agonists at high IA is very blurred. I suspect it is the same deal with superagonists. For example take the 5HT1a ligand eptapirone. A good number of studies show certain analogs as having 110%+ IA. In other studies, however, it is still only classified as a full agonist. I would suspect precision in measurements is the cause but who knows?

I've always been confused about the 5HT-2a receptor's functional selectivity. Why does this occur? Which pathways does the natural ligand (serotonin) activate? Would 5-methoxy-Tryptamine or 5-carboxamido-tryptamine have some psychedelic effect if administered with antagonists for other 5HT receptors?
 
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