Inverse agonism and its therapeutic significance

Abstract

A large number of G-protein-coupled receptors (GPCRs) show varying degrees of basal or constitutive activity. This constitutive activity is usually minimal in natural receptors but is markedly observed in wild type and mutated (naturally or induced) receptors. According to conventional two-state drug receptor interaction model, binding of a ligand may initiate activity (agonist with varying degrees of positive intrinsic activity) or prevent the effect of an agonist (antagonist with zero intrinsic activity). Inverse agonists bind with the constitutively active receptors, stabilize them, and thus reduce the activity (negative intrinsic activity). Receptors of many classes (α-and β-adrenergic, histaminergic, GABAergic, serotoninergic, opiate, and angiotensin receptors) have shown basal activity in suitable in vitro models. Several drugs that have been conventionally classified as antagonists (β-blockers, antihistaminics) have shown inverse agonist effects on corresponding constitutively active receptors. Nearly all H(1) and H(2) antihistaminics (antagonists) have been shown to be inverse agonists. Among the β-blockers, carvedilol and bucindolol demonstrate low level of inverse agonism as compared to propranolol and nadolol. Several antipsychotic drugs (D(2) receptors antagonist), antihypertensive (AT(1) receptor antagonists), antiserotoninergic drugs and opioid antagonists have significant inverse agonistic activity that contributes partly or wholly to their therapeutic value. Inverse agonism may also help explain the underlying mechanism of beneficial effects of carvedilol in congestive failure, naloxone-induced withdrawal syndrome in opioid dependence, clozapine in psychosis, and candesartan in cardiac hypertrophy. Understanding inverse agonisms has paved a way for newer drug development. It is now possible to develop agents, which have only desired therapeutic value and are devoid of unwanted adverse effect. Pimavanserin (ACP-103), a highly selective 5-HT(2A) inverse agonist, attenuates psychosis in patients with Parkinson's disease with psychosis and is devoid of extrapyramidal side effects. This dissociation is also evident from the development of anxioselective benzodiazepines devoid of habit-forming potential. Hemopressin is a peptide ligand that acts as an antagonist as well as inverse agonist. This agent acts as an antinociceptive agent in different in vivo models of pain. Treatment of obesity by drugs having inverse agonist activity at CB(1/2) receptors is also underway. An exciting development is evaluation of β-blockers in chronic bronchial asthma-a condition akin to congestive heart failure where β-blockade has become the standard mode of therapy. Synthesis and evaluation of selective agents is underway. Therefore, inverse agonism is an important aspect of drug-receptor interaction and has immense untapped therapeutic potential.

Keywords: Constitutive activity; G-protein-coupled receptors; inverse agonism; inverse agonists.

Figure 1

Conventional two-state model of drug–receptor interaction

Figure 2

Intrinsic activities of full agonist, antagonist, and inverse agonists

Figure 3

Constitutively active receptor and inverse agonism

Figure 4

Proposed drug–receptor model to explain inverse agonism

Figure 5

Inverse agonist-receptor interaction

Box 1

Transfection: An in-vitro method to study receptor function