Structure-Activity Relationships of Phenylalkylamines as Agonist Ligands for 5-HT2A Receptors

• Published in: ChemMedChem 2008-09, Vol.3 (9), p.1299-1309
• Main Authors: Blaazer, Antoni R., Smid, Pieter, Kruse, Chris G.
• Format: Article
• Language: English
• Subjects: 5-HT2A receptors; drug design; phenylalkylamines; serotonin; structure-activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200800133

Agonist activation of central 5‐HT2A receptors results in diverse effects, such as hallucinations and changes of consciousness. Recent findings indicate that activation of the 5‐HT2A receptor also leads to interesting physiological responses, possibly holding therapeutic value. Selective agonists are needed to study the full therapeutic potential of this receptor. 5‐HT2A ligands with agonist profiles are primarily derived from phenylalkylamines, indolealkylamines, and certain piperazines. Of these, phenylalkylamines, most notably substituted phenylisopropylamines, are considered the most selective agonists for 5‐HT2 receptors. This review summarizes the structure–activity relationships (SAR) of phenylalkylamines as agonist ligands for 5‐HT2A receptors. Selectivity is a central theme, as is selectivity for the 5‐HT2A receptor and for its specific signaling pathways. SAR data from receptor affinity studies, functional assays, behavioral drug discrimination as well as human studies are discussed. Agonist activation of 5‐HT2A receptors has become therapeutically interesting. Substituted phenylalkylamines are the most suitable agonists for the study of 5‐HT2A receptor activation. This minireview summarizes the structure–activity relationships of phenylalkylamines as agonist ligands for the 5‐HT2A receptor.