Partial agonist

Agonists

A partial agonist in the presence of a full agonist or a stronger partial agonist blocks the binding of the agonist molecule to the receptor , inhibiting the signal from the receptor-agonist interaction.

Dose-response curves for a complete agonist , partial agonist, neutral antagonist and inverse agonist

In pharmacology, the term partial agonists (the term “ partial agonist ” is also used) is used to refer to drugs and chemical compounds that are ligands for a particular subtype of cellular receptors (that is, bind to them) and are able to activate the receptor, that is, translate it into an active spatial configuration (exhibit agonistic properties), but with a lower probability (less receptor efficiency ) than an endogenous agonist of the same receptors, receptor efficiency otorogo is taken as 100% and which is thus considered as a true complete agonist . In other words, the internal agonistic activity of a partial agonist (synonymous with its “receptor efficacy”) is by definition always greater than 0% (otherwise it would be a “ neutral antagonist ”), but less than 100% (otherwise it would be a “complete agonist”).

In practice, the internal agonistic activity of substances usually considered as “partial agonists” is usually higher than 10–20%, but lower than 70–80%, since “weak” partial agonists (with internal agonistic activity less than 10–20%) both experimentally and in clinical practice it is usually difficult to distinguish from “true” neutral antagonists (having strictly zero internal agonistic activity), and “strong” partial agonists (with internal agonistic activity greater than 70-90%) are difficult to distinguish from “true” full ag oily (having an inner agonistic activity strictly equal to 100%). Moreover, there are, in fact, very few “true” neutral antagonists (with strictly zero internal agonistic activity) - most of them are either weak and very weak partial agonists, or inverse agonists . In the same way, there are very few “true” complete agonists (except for the endogenous agonist, which by definition is 100%) - most of them are simply strong or very strong partial agonists. Moreover, even if in an experiment for a certain compound an internal agonistic activity value of exactly 0% or 100% is obtained, this does not mean at all that this compound is really a “true neutral antagonist” or a “true complete agonist” - it’s just means that the difference between the measured value and 0% or 100% is less than the error of the measurement method. Thus, from a formal mathematical point of view, partial agonists are the most common type of exogenous ligands, and depending on the size of the internal agonistic activity, they can be clinically considered and used either as quasi- “antagonists” (weak partial agonists with an internal agonistic activity of less than 10-20% of the activity of the endogenous ligand), or as a quasi-“complete agonist” (strong partial agonists with an internal agonistic activity above 70-90% of the active endogenous ligand), or as “partial agonists” (with intermediate values ​​of internal agonistic activity).

Partial agonists can also be considered as ligands that exhibit both agonistic and antagonistic properties depending on the specific clinical or experimental situation, or, in other words, as “mixed antagonist agonists”. Namely, when a partial agonist and a complete agonist (for example, an endogenous agonist) or just a stronger partial agonist of the same receptors are present in the biological system , the “weaker” partial agonist, in fact, exhibits the properties of a competitive antagonist of these receptors competing with a "stronger" partial agonist or with a full agonist (including an endogenous ligand) for receptor occupation and, thus, causing a general decrease in the level of activity of the receptor system compared to the existence of only one complete agonist or "stronger" partial agonist in the same concentration. ^{[1] The} clinical benefit and effectiveness of partial agonists is determined by the fact that they can simultaneously activate receptor systems with insufficient stimulation (low level of endogenous full agonist) to some desired “submaximal” level (which is lower than when using a full agonist), and to prevent excessive, excessive, and harmful receptor hyperstimulation that occurs with an excessively high level of endogenous agonist. ^[2] The ability of partial agonists to act as competitive antagonists in the presence of a full agonist (including an endogenous ligand) or in the presence of a “stronger" partial agonist is very important for clinical practice. For example, the ability of naloxone (which is not really a true antagonist, but a very, very weak partial agonist of opioid receptors - is so weak that its partial agonistic activity has no clinical significance and is traditionally referred to as opioid antagonists) to relieve manifestations of opioid intoxication based precisely on this property. No less important for clinical practice is the ability of strong partial agonists (with receptor efficacy of 80-90% and higher) to act almost indistinguishable from “true” full agonists. So, for example, the pressor substance phenylephrine (mesatone), which is a structural analogue of norepinephrine , is actually a very strong, “almost complete” partial agonist of α-adrenergic receptors, and not a “true” complete agonist. But this difference is so small that it has no clinical significance and allows the use of phenylephrine as an "almost complete agonist", a pressor substance for the relief of hypotension , instead of short-acting and inconvenient for the use of norepinephrine. Similarly, salbutamol is a strong, “almost complete” partial β-adrenoreceptor agonist, so strong that its effect on the bronchi is clinically indistinguishable from adrenaline , which allows it to be used as a bronchodilator.

Other important examples of drugs that are partial agonists of one or another receptor (and in the true, “balanced” sense - not in the sense of similarity to the extreme examples above with naloxone and phenylephrine and salbutamol) include non-benzodiazepine anxiolytic buspirone , atypical antipsypsychotic opioid receptor agonist narcotic analgesic buprenorphine , clozapine metabolite norklosapine. There are also examples of ligands that activate the PPARγ receptor precisely as partial agonists — honokiol and falkarindiol. ^{[3] [4]}