Received for publication December 1, 2006.
Revised February 28, 2007.
Accepted for publication February 28, 2007.

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-HT_2A and 5-HT_2C Receptors

Abstract

2,5-dimethoxy-4-substituted phenylisopropylamines and phenethylamines are serotonin_2A/2C (5-HT_2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors (e.g. phospholipase A₂ (PLA₂)) are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA₂ and PLC responses in CHO-K1 cells expressing human 5-HT_2A or 5 HT_2C receptors. Also, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT_2C receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses as compared to their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT_2A receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT_2C receptor, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-DMA (2,5-dimethoxyphenylisopropylamine) activated only the PLC pathway at both receptor subtypes, 2C-H (2,5-dimethoxyphenethylamine) was selective for PLC at the 5-HT_2C receptor, and 2C-N (2,5-dimethoxy-4-nitrophenethylamine) was PLA₂-specific at the 5-HT_2A receptor. For both receptors, the compounds' rank order of efficacy differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT_2A receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

Key words: efficacy, functional selectivity, hallucinogens, serotonin receptors, signal transduction, stimulus trafficking

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