Agonist-Trafficking and Hallucinogens
Current Medicinal Chemistry – March 01, 2009
Source: OpenAlex
Summary
Psychedelics like Lysergic acid diethylamide (LSD), psilocybin, and mescaline profoundly influence behavior as hallucinogens, despite chemically similar compounds showing no such effect. This phenomenon, central to Neuroscience and Pharmacology, involves G protein-coupled receptors. Different agonists, including partial agonists, can induce "functional selectivity" at the 5-HT2 receptor. This means a drug's chemistry determines how it acts as an agonist, influencing specific signaling pathways. Understanding this receptor mechanism is crucial for drug studies, revealing how chemical synthesis and alkaloids impact neurotransmitter receptor influence on behavior.
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-HT(2A) 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.