Di erences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT2A and 5-HT2C receptors

Abstract

1 The pharmacological pro®le of a series of (+)-2,5-dimethoxy-4-(X)-phenylisopropylamines (X=I, Br, NO2, CH3, or H) and corresponding phenylethylamines, was determined in Xenopus laevis oocytes injected with cRNA coding for rat 5-HT2A or 5-HT2C receptors. The e cacy and relative potency of these drugs were determined and compared to classical 5-HT2 receptor agonists and antagonists. 2 The rank order of agonist potency at the 5-HT2A receptor was: a-methyl-5-HT=5-HT4m- CPP4MK-212; at the 5-HT2C receptor the order was: 5-HT4a-methyl-5-HT4MK-2124m-CPP. All these compounds were full agonists at the 5-HT2C receptor, but a-methyl-5-HT and m-CPP showed lower e cacy at the 5-HT2A receptor. 3 4-(4-Fluorobenzoyl)-1-(4-phenylbutyl)piperidine (4F 4PP) was 200 times more potent as a 5- HT2A antagonist than at 5-HT2C receptors. Conversely, RS 102221 was 100 times more potent as a 5-HT2C antagonist, con®rming their relative receptor selectivities. 4 The phenylisopropylamines were partial agonists at the 5-HT2A receptor, with Imax relative to 5- HT in the 22+7 to 58+15% range; the corresponding phenylethylamines had lower or undetectable e cacies. All these drugs had higher e cacies at 5-HT2C receptors; DOI was a full 5-HT2C agonist. 2C-I and the other phenylethylamines examined showed relative e cacies at the 5-HT2C receptor ranging from 44+10% to 76+16%. 5 2C-N was a 5-HT2 receptor antagonist; the mechanism was competitive at the 5-HT2A, but non- competitive at the 5-HT2C receptor. The antagonism was time-dependent at the 5-HT2C receptor but independent of pre-incubation time at the 5-HT2A receptor subtype. 6 The a-methyl group determines the e cacy of these phenylalkylamines at the 5-HT2A and 5- HT2C receptors.