"Selective" serotonin 5-HT2A receptor antagonists

Abstract

Blockade of the serotonin 5-HT_2A G protein-coupled receptor (5-HT_2AR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT_2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT_2AR agonists, however, often bind other receptors, and standard 5-HT_2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT_2AR-dependent effects of these compounds and the general neurobiological function of 5-HT_2ARs. This review discusses the limitations and strengths of currently available "selective" 5-HT_2AR antagonists, the molecular determinants of antagonist selectivity at 5-HT_2ARs, and the utility of molecular pharmacology and computational methods in guiding the discovery of novel unambiguously selective 5-HT_2AR antagonists.

Keywords: 5-HT(2A); Antagonist; Antipsychotic; GPCR; Selectivity.