Receptor antagonist
The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.
[2] The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, competitor, villain, enemy, rival", which is derived from anti- ("against") and agonizesthai ("to contend for a prize").
[3][4] Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug.
[7] In addition, antagonists may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity to exert their effects.
[7][8][9] The term antagonist was originally coined to describe different profiles of drug effects.
It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor.
Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell.
The affinity constant of antagonists exhibiting two or more effects, such as in competitive neuromuscular-blocking agents that also block ion channels as well as antagonising agonist binding, cannot be analyzed using Schild regression.
Sufficient concentrations of an antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation.
[17] In functional assays using competitive antagonists, a parallel rightward shift of agonist dose–response curves with no alteration of the maximal response is observed.
Naloxone (also known as Narcan) is used to reverse opioid overdose caused by drugs such as heroin or morphine.
[22] While the mechanism of antagonism is different in both of these phenomena, they are both called "non-competitive" because the end-results of each are functionally very similar.
In functional assays of non-competitive antagonists, depression of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced.
[29] Memantine, used in the treatment of Alzheimer's disease, is an uncompetitive antagonist of the NMDA receptor.
[32][33] Clinically, their usefulness is derived from their ability to enhance deficient systems while simultaneously blocking excessive activity.
In addition, it has been suggested that partial agonism prevents the adaptive regulatory mechanisms that frequently develop after repeated exposure to potent full agonists or antagonists.
[34][35] E.g. Buprenorphine, a partial agonist of the μ-opioid receptor, binds with weak morphine-like activity and is used clinically as an analgesic in pain management and as an alternative to methadone in the treatment of opioid dependence.
[36] An inverse agonist can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses.
Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors.
[37][38] Antihistamines, originally classified as antagonists of histamine H1 receptors have been reclassified as inverse agonists.
[16] For some antagonists, there may be a distinct period during which they behave competitively (regardless of basal efficacy), and freely associate to and dissociate from the receptor, determined by receptor-ligand kinetics.
