Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors.
Claudio Acuña-Castillo, Claudio Villalobos, Pablo R Moya, Patricio Sáez, Bruce K Cassels, J Pablo Huidobro-Toro
British journal of pharmacology June 1, 2002 DOI: 10.1038/sj.bjp.0704747 via PubMed
Summary
AI-generated from the abstractA series of phenylisopropylamines and phenylethylamines were tested on rat serotonin 5-HT2A and 5-HT2C receptors expressed in frog eggs. All compounds acted as full agonists at 5-HT2C receptors, while at 5-HT2A receptors they were partial agonists, with relative efficacy ranging from 22% to 58% of serotonin's effect. The phenylethylamines had lower or undetectable efficacy at 5-HT2A receptors. DOI was a full agonist at 5-HT2C, while 2C-N acted as an antagonist at both receptors, competitive at 5-HT2A but non-competitive at 5-HT2C. The alpha-methyl group on the drugs determined their efficacy at both receptor subtypes.
Study at a glance
| Characteristics | Laboratory experiment Peer reviewed |
|---|---|
| Population | Xenopus laevis oocytes injected with rat 5-HT2A or 5-HT2C receptor cRNA |
| Interventions | 2C-N 4F 4PP RS 102221 |
| Key finding | The alpha-methyl group determines the efficacy of phenylalkylamines at 5-HT2A and 5-HT2C receptors, with all tested compounds being full agonists at 5-HT2C but partial agonists at 5-HT2A. |
Abstract
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: alpha-methyl-5-HT=5-HT>m-CPP>MK-212; at the 5-HT(2C) receptor the order was: 5-HT>alpha-methyl-5-HT>MK-212>m-CPP. All these compounds were full agonists at the 5-HT(2C) receptor, but alpha-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 alpha-methyl group determines the efficacy of these phenylalkylamines at the 5-HT(2A) and 5-HT(2C) receptors.