A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex which in turn depends on the nature of antagonist receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand (such as a hormone or drug). Receptors can be membrane-bound, occurring on the cell membrane of cells, or intracellular, such as on the nucleus or mitochondrion. Binding occurs as a result of noncovalent interaction between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly. The activity of receptors can also be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the active site or the allosteric site. 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.
The term antagonist was originally coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model. 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. Antagonists were thought to turn "off" that response by 'blocking' the receptor from the agonist. This definition also remains in use for physiological antagonists, substances which have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by β-adrenergic receptor activation.
Our understanding of the mechanism of drug induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two state model of receptor activation has given way to multistate models with intermediate conformational states. The discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may actually depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug.
Partial agonists are defined as drugs which, at a given receptor, might differ in the amplitude of the functional response that they elicit after maximal receptor occupancy. Although they are agonists, partial agonists can act as a competitive antagonist if co-administered with a full agonist, as it competes with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone. Clinically, their usefulness is derived from their ability to enhance deficient systems while simultaneously blocking excessive activity. Exposing a receptor to a high level of a partial agonist will ensure that it has a constant, weak level of activity, whether its normal agonist is present at high or low levels. 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. 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 in reversing morphine addiction as an alternative to methodone in the treatment of drug addiction. An inverse agonist can have effects similar to an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors which exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist, but inhibit the basal activity of the receptor. Drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors. Antihistamines, originally classified as antagonists of histamine H1 receptors have been reclassified as inverse agonists.
Irreversible antagonists covalently bind to the receptor target and generally cannot be removed; inactivating the receptor for the duration of the antagonist effects is determined by the rate of receptor turnover, the rate of synthesis of new receptors. Phenoxybenzamine is an example of an irreversible alpha blocker—it permanently binds to α adrenergic receptors, preventing adrenaline and noradrenaline from binding. Inactivation of receptors normally results in a depression of the maximal response of agonist dose-response curves and a right shift in the curve occurs where there is a receptor reserve similar to non-competitive antagonists. A washout step in the assay will usually distinguish between non-competitive and irreversible antagonist drugs as effects of non-competitive antagonists are reversible and activity of agonist will be restored.
Irreversible competitive antagonists also involve competition between the agonist and antagonist of the receptor, but the rate of covalent bonding differs and depends on affinity and reactivity of the antagonist. For some antagonist there may be a distinct period in which they behave competitively (regardless of basal efficiacy), and freely associate to and dissociate from the receptor, determined by receptor-ligand kinetics. But once irreversible bonding has taken place, the receptor is deactivated and degraded. As for non-competitive antagonists and irreversible antagonists in functional assays with irreversible competitive antagonist drugs, there may be a shift in the log concentration–effect curve to the right, but generally both a decrease in slope and reduced maximum are obtained.
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