Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5‐HT 2A and 5‐HT 2C receptors

The pharmacological profile of a series of (±)‐2,5‐dimethoxy‐4‐(X)‐phenylisopropylamines (X=I, Br, NO 2 , CH 3 , or H) and corresponding phenylethylamines, was determined in Xenopus laevis oocytes injected with cRNA coding for rat 5‐HT 2A or 5‐HT 2C receptors. The efficacy and relative potency of these drugs were determined and compared to classical 5‐HT 2 receptor agonists and antagonists. The rank order of agonist potency at the 5‐HT 2A receptor was: α‐methyl‐5‐HT=5‐HT> m ‐CPP>MK‐212; at the 5‐HT 2C receptor the order was: 5‐HT>α‐methyl‐5‐HT>MK‐212> m ‐CPP. All these compounds were full agonists at the 5‐HT 2C receptor, but α‐methyl‐5‐HT and m ‐CPP showed lower efficacy at the 5‐HT 2A receptor. 4‐(4‐Fluorobenzoyl)‐1‐(4‐phenylbutyl)piperidine (4F 4PP) was 200 times more potent as a 5‐HT 2A antagonist than at 5‐HT 2C receptors. Conversely, RS 102221 was 100 times more potent as a 5‐HT 2C antagonist, confirming their relative receptor selectivities. The phenylisopropylamines were partial agonists at the 5‐HT 2A receptor, with I max relative to 5‐HT in the 22±7 to 58±15% range; the corresponding phenylethylamines had lower or undetectable efficacies. All these drugs had higher efficacies at 5‐HT 2C receptors; DOI was a full 5‐HT 2C agonist. 2C‐I and the other phenylethylamines examined showed relative efficacies at the 5‐HT 2C receptor ranging from 44±10% to 76±16%. 2C‐N was a 5‐HT 2 receptor antagonist; the mechanism was competitive at the 5‐HT 2A , but non‐competitive at the 5‐HT 2C receptor. The antagonism was time‐dependent at the 5‐HT 2C receptor but independent of pre‐incubation time at the 5‐HT 2A receptor subtype. The α‐methyl group determines the efficacy of these phenylalkylamines at the 5‐HT 2A and 5‐HT 2C receptors.British Journal of Pharmacology (2002) 136 , 510–519; doi: 10.1038/sj.bjp.0704747