MobiusDick
Bluelighter
Ligand/Receptor Interactions; Partial & Inverse Agonism; Pharmacologic vs Physiologic
Many people seem to need a pharmacology lesson about ligand/receptor interactions. As many of the pharmaceutical sciences students, but particularly medical students I teach, do not seem to have a good grasp these concepts, a few pharmacologists have gotten together and tried to clarify this, hopefully before the next edition of Goodman & Gilman's The Pharmacological Basis of Therapeutics (the Bible of modern pharmacology and pharmaceutical sciences textbooks.) If you are beyond the point of needing this information, don't be offended. If you read this to the end you may be surprised at some of the concepts.
Back to the essay: The ligand is the binding agent or molecule aka the drug and the receptor is the molecule or molecular complex to which the ligand binds. Most of you have heard of agonists and antagonists, but what really need clearing up are the concepts of mixed agonist/antagonists, partial agonists and inverse agonists. This is the fault of medical writers of drug companies who initially confused mixed agonist/antagonists and partial agonists in their package inserts.
An agonist is a drug that binds to a receptor ephemerally, stimulates it (known as transduction) and then releases from it; for a drug to be a full agonist, it must release from the receptor almost immediately after transducing it. If it stays bound to the receptor after transducing it, it is then a partial agonist and not a full agonist. Drugs like codeine and propoxyphene, even though they do not have as strong an analgesic (aka pain relieving) effect, are full agonists, although they are weak agonists. The reason that these drugs are not as effective as analgesics as morphine or oxycodone is not because of the way they bind to their receptors; rather it is because the affinity they have to bind to the receptor in the first place (which I will say a little more about after explaining antagonists,) as well as the subset of receptors with which they bind.
A partial agonist, like buprenorphine, is not called partial because it only partially activates the receptor. When a partial agonist binds a receptor, it transduces or stimulates it (and in this sense acts like a full agonist), but then it stays bound to the receptor for (almost always) a non-linear amount of time (and in this sense acts like an antagonist.) Note that this non-linear amount of time is known as the dissociation half-life (td½), and is not related in any way to the elimination half-life or the effective half-life of a drug other than the elimination half-life must be greater than the dissociation half-life. The dissociation half-life literally means the length of time required for one half (50%) of the bound drug to dissociate from the receptor. It is non-linear because the number of molecules of the drug that release from the receptor in a given amount of time changes (increases) the more of the drug that is bound. (For buprenorphine, the dissociation half-life is 4 hours meaning that half of the bound molecules of buprenorphine will release from the receptor over the course of every 4 hours {however, this does not occur all at once when the clock hits 4 hours.}) ***Just as an aside, if the time for a set number of molecules to dissociate were linear, the value would be called the dissociation constant, and it would mean that a constant number of molecules release from the receptor in a certain amount of time, like 100 molecules per 4 hours, instead of a constant percentage in given time, like 50% per 4 hours, when the kinetics are non-linear. Only a few drugs that bind reversibly to the receptor, behave in this way. ***
But here is an important fundamental aspect of partial agonism: In the presence of an initial full agonist, a partial agonist MUST behave as a non-competitive antagonist (which will be explained in the next two sections.) In addition, a partial agonist is also a partial antagonist, and the longer the dissociation half-life is, the more like an antagonist the drug behaves and the less like an agonist. The shorter the dissociation half-life, the more like an agonist the drug behaves and the less like an antagonist.
A full antagonist binds to a receptor, but does not transduce or stimulate the receptor; then, depending on the type of antagonist, it behaves in one of three ways: In the case of an irreversible antagonist like β-funaltrexate, the antagonist stays bound permanently (covalently) to the receptor and blocks it from any further stimulation by an agonist (meaning that the receptor will no longer {ever} be able to be transduced.) And until the blocked receptor is internalized and a new one made, the irreversible antagonist will remain attached to the receptor. With an irreversible antagonist, no matter how high a concentration of agonist you subject the receptors to after exposure to a high concentration of the antagonist (called the IC50 or IC100 —meaning the Inhibitory Concentration in 50% or 100% of your sample population,) there will be no agonist activity.
Then there are two more types of antagonists, non-competitive and competitive (although technically, irreversible antagonists are really a type of non-competitive antagonist.) Non-competitive antagonists, like naloxone and naltrexone, bind to the receptor and do not stimulate it. Then they (almost always) stay bound for a non-linear amount of time (i.e., it obeys First Order Kinetics.) This is also known as the dissociation half-life (or dissociation constant in the rare case where the ligand/receptor interaction obeys linear {Zero Order}kinetics, before releasing from the receptor. This binding is usually ionic and not covalent, unlike the irreversible antagonists, and during the bound time, an agonist cannot stimulate the receptor. However, as long as the antagonist binds reversibly, then by increasing the dose of the agonist high enough, you can reverse SOME of the effect of the antagonist. This is because at a very high concentration of agonist relative to antagonist, the probability of many agonist bindings to and transductions of the receptors, each time an antagonist releases can be made to occur before another antagonist binds; however, until all of a non-competitive antagonist is inactivated or excreted, there will always be some effect that the antagonist exerts, unlike with our final type of antagonist.
With a competitive antagonist, the molecule basically just fits into the receptor and competes with the agonist, keeping it from binding and stimulating the receptor. Any binding that occurs to the receptor with a competitive antagonist is hydrogen bonding and not covalent or ionic, and the effect of the competitive antagonist can be completely reversed by using a high enough dose of agonist. (Also note two additional principles that arise from this concept: partial agonists cannot behave as competitive antagonists during their antagonism phase because you would not be able to differentiate this behavior from that of a weak agonist; and all drugs act like competitive antagonists with themselves when they do not bind in the right conformation to transduce the receptor. This happens a lot more with codeine than with fentanyl (i.e., far more interactions of fentanyl with the receptor result in transduction than do the interactions of codeine with the receptor. This is one way that different drugs have different molar effective doses {in other words, this is one of the reasons that the same number of molecules of fentanyl cause such a larger effect than the same number of molecules of codeine when given as an iv bolus; some other reasons have to do with the subpopulation of receptors to which fentanyl binds; and of course biopharmaceutics and pharmacokinetics principles such as octanol/water partition coefficients and active uptake across the blood brain barrier.}
End of Part 1
Many people seem to need a pharmacology lesson about ligand/receptor interactions. As many of the pharmaceutical sciences students, but particularly medical students I teach, do not seem to have a good grasp these concepts, a few pharmacologists have gotten together and tried to clarify this, hopefully before the next edition of Goodman & Gilman's The Pharmacological Basis of Therapeutics (the Bible of modern pharmacology and pharmaceutical sciences textbooks.) If you are beyond the point of needing this information, don't be offended. If you read this to the end you may be surprised at some of the concepts.
Back to the essay: The ligand is the binding agent or molecule aka the drug and the receptor is the molecule or molecular complex to which the ligand binds. Most of you have heard of agonists and antagonists, but what really need clearing up are the concepts of mixed agonist/antagonists, partial agonists and inverse agonists. This is the fault of medical writers of drug companies who initially confused mixed agonist/antagonists and partial agonists in their package inserts.
An agonist is a drug that binds to a receptor ephemerally, stimulates it (known as transduction) and then releases from it; for a drug to be a full agonist, it must release from the receptor almost immediately after transducing it. If it stays bound to the receptor after transducing it, it is then a partial agonist and not a full agonist. Drugs like codeine and propoxyphene, even though they do not have as strong an analgesic (aka pain relieving) effect, are full agonists, although they are weak agonists. The reason that these drugs are not as effective as analgesics as morphine or oxycodone is not because of the way they bind to their receptors; rather it is because the affinity they have to bind to the receptor in the first place (which I will say a little more about after explaining antagonists,) as well as the subset of receptors with which they bind.
A partial agonist, like buprenorphine, is not called partial because it only partially activates the receptor. When a partial agonist binds a receptor, it transduces or stimulates it (and in this sense acts like a full agonist), but then it stays bound to the receptor for (almost always) a non-linear amount of time (and in this sense acts like an antagonist.) Note that this non-linear amount of time is known as the dissociation half-life (td½), and is not related in any way to the elimination half-life or the effective half-life of a drug other than the elimination half-life must be greater than the dissociation half-life. The dissociation half-life literally means the length of time required for one half (50%) of the bound drug to dissociate from the receptor. It is non-linear because the number of molecules of the drug that release from the receptor in a given amount of time changes (increases) the more of the drug that is bound. (For buprenorphine, the dissociation half-life is 4 hours meaning that half of the bound molecules of buprenorphine will release from the receptor over the course of every 4 hours {however, this does not occur all at once when the clock hits 4 hours.}) ***Just as an aside, if the time for a set number of molecules to dissociate were linear, the value would be called the dissociation constant, and it would mean that a constant number of molecules release from the receptor in a certain amount of time, like 100 molecules per 4 hours, instead of a constant percentage in given time, like 50% per 4 hours, when the kinetics are non-linear. Only a few drugs that bind reversibly to the receptor, behave in this way. ***
But here is an important fundamental aspect of partial agonism: In the presence of an initial full agonist, a partial agonist MUST behave as a non-competitive antagonist (which will be explained in the next two sections.) In addition, a partial agonist is also a partial antagonist, and the longer the dissociation half-life is, the more like an antagonist the drug behaves and the less like an agonist. The shorter the dissociation half-life, the more like an agonist the drug behaves and the less like an antagonist.
A full antagonist binds to a receptor, but does not transduce or stimulate the receptor; then, depending on the type of antagonist, it behaves in one of three ways: In the case of an irreversible antagonist like β-funaltrexate, the antagonist stays bound permanently (covalently) to the receptor and blocks it from any further stimulation by an agonist (meaning that the receptor will no longer {ever} be able to be transduced.) And until the blocked receptor is internalized and a new one made, the irreversible antagonist will remain attached to the receptor. With an irreversible antagonist, no matter how high a concentration of agonist you subject the receptors to after exposure to a high concentration of the antagonist (called the IC50 or IC100 —meaning the Inhibitory Concentration in 50% or 100% of your sample population,) there will be no agonist activity.
Then there are two more types of antagonists, non-competitive and competitive (although technically, irreversible antagonists are really a type of non-competitive antagonist.) Non-competitive antagonists, like naloxone and naltrexone, bind to the receptor and do not stimulate it. Then they (almost always) stay bound for a non-linear amount of time (i.e., it obeys First Order Kinetics.) This is also known as the dissociation half-life (or dissociation constant in the rare case where the ligand/receptor interaction obeys linear {Zero Order}kinetics, before releasing from the receptor. This binding is usually ionic and not covalent, unlike the irreversible antagonists, and during the bound time, an agonist cannot stimulate the receptor. However, as long as the antagonist binds reversibly, then by increasing the dose of the agonist high enough, you can reverse SOME of the effect of the antagonist. This is because at a very high concentration of agonist relative to antagonist, the probability of many agonist bindings to and transductions of the receptors, each time an antagonist releases can be made to occur before another antagonist binds; however, until all of a non-competitive antagonist is inactivated or excreted, there will always be some effect that the antagonist exerts, unlike with our final type of antagonist.
With a competitive antagonist, the molecule basically just fits into the receptor and competes with the agonist, keeping it from binding and stimulating the receptor. Any binding that occurs to the receptor with a competitive antagonist is hydrogen bonding and not covalent or ionic, and the effect of the competitive antagonist can be completely reversed by using a high enough dose of agonist. (Also note two additional principles that arise from this concept: partial agonists cannot behave as competitive antagonists during their antagonism phase because you would not be able to differentiate this behavior from that of a weak agonist; and all drugs act like competitive antagonists with themselves when they do not bind in the right conformation to transduce the receptor. This happens a lot more with codeine than with fentanyl (i.e., far more interactions of fentanyl with the receptor result in transduction than do the interactions of codeine with the receptor. This is one way that different drugs have different molar effective doses {in other words, this is one of the reasons that the same number of molecules of fentanyl cause such a larger effect than the same number of molecules of codeine when given as an iv bolus; some other reasons have to do with the subpopulation of receptors to which fentanyl binds; and of course biopharmaceutics and pharmacokinetics principles such as octanol/water partition coefficients and active uptake across the blood brain barrier.}
End of Part 1
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