Current Medicinal Chemistry

Atta-ur-Rahman, FRS
Honorary Life Fellow
Kings College
University of Cambridge
Cambridge
UK

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Agonist-Trafficking and Hallucinogens

Author(s): Javier Gonzalez-Maeso and Stuart C. Sealfon

Affiliation: Departments of Psychiatry, Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Abstract:

Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT2A receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

Keywords: Agonist-Trafficking, Hallucinogens, G protein-coupled receptors (GPCRs), lysergic acid diethylamide (LSD), hallucinogenic drugs

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Article Details

VOLUME: 16
ISSUE: 8
Page: [1017 - 1027]
Pages: 11
DOI: 10.2174/092986709787581851
Price: $58