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Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT 2A and 5-HT 2C receptors
Keywords: aniline, hydrogen, serotonin, antagonists, binding, cell, structure, 2a, mechanism, alpha, efficacy, laevis, agonist, receptor, patch-clamp, vitro, methyl, selectivity, xenopus, nitro, agonists, oocytes, female, iodine, affinity, drug, article, antagonist, nitrite, activity, phenethylamine, potency, techniques, group, controlled, animal, relation, study, 4, 8, 1, compounds, phenethylamines, relationship, derivative, amino, priority, in, nonhuman, journal, Receptors,, Structure-Activity, 2, (1, (2,5, dimethoxy, aminopropane, 2,5, (3, unclassified, 2,4, 5, 6, (4, Bromine, bromo, dione, [4, methylserotonin, Ethylamines, iodo, chloro, (5, Support,, Non-U.S., Gov't, 2C, Propylamines, chlorophenyl)piperazine, nitrophenyl), iodophenylethylamine, methylphenylethylamine, nitrophenylethylamine, phenylisopropylamine, trifluoromethylphenylethylamine, dimethoxyphenylethylamine, fluorobenzoyl), phenylbutyl)piperidine, dimethoxyamphetamine, piperazinyl)pyrazine, dimethoxybenzoyl)butyl], 1,3,8, triazaspiro[4.5]decane, [5, [2,4, trifluoromethylphenyl)sulfonamido]phenyl, oxopentyl], triazaspiro[4,5]decane, propylamine
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: ?-methyl-5-HT=5-HT > m-CPP > MK-212; at the 5-HT 2C receptor the order was: 5-HT > ?-methyl-5-HT > MK-212 > m-CPP. All these compounds were full agonists at the 5-HT 2C receptor, but ?-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 ?-methyl group determines the efficacy of these phenylalkylamines at the 5-HT 2A and 5-HT 2C receptors.
Más información
| Título de la Revista: | BRITISH JOURNAL OF PHARMACOLOGY |
| Volumen: | 136 |
| Número: | 4 |
| Editorial: | Wiley |
| Fecha de publicación: | 2002 |
| Página de inicio: | 510 |
| Página final: | 519 |
| URL: | http://www.scopus.com/inward/record.url?eid=2-s2.0-0035984936&partnerID=q2rCbXpz |