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

1 The pharmacological profile 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 efficacy 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: alpha-methyl-5-HT = 5-HT > m- CPP>MK-212: at the 5-HT2C receptor the order was: 5-HT>alpha-methyl-5-HT>MK-212>m-CPP. All these compounds were full agonists at the 5-HT2C receptor, but alpha-methyl-5-HT and m-CPP showed lower efficacy 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, confirming their relative receptor selectivities. 4 The phenylisopropylamines were partial agonists at the 5-HT2A 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-HT2C receptors; DOI was a full 5-HT2C agonist. 2C-I and the other phenylethylamines examined showed relative efficacies at the 5-HT2C receptor ranging from 44+/-10% to 76+/-16%. 1; 2C-N was a 5-HT2 receptor antagonist; the mechanism was competitive at the 5-HT2A, but noncompetitive 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 alpha-methyl group determines the efficacy of these phenylalkylamines at the 5-HT2A and 5-HT2C receptors.