4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes.
1. We recently described that several 2-(2,5-dimethoxy-4-substituted phenyl)ethylamines (PEAs), including 4-I=2C-I, 4-Br=2C-B, and 4-CH(3)=2C-D analogs, are partial agonists at 5-HT(2C) receptors, and show low or even negligible intrinsic efficacy at 5-HT(2A) receptors. These results raised the proposal that these drugs may act as 5-HT(2) antagonists. 2. To test this hypothesis, Xenopus laevis oocytes were microinjected with the rat clones for 5-HT(2A) or 5-HT(2C) receptors. The above-mentioned PEAs and its 4-H analog (2C-H) blocked the 5-HT-induced currents at 5-HT(2A), but not at the 5-HT(2C) receptor, revealing 5-HT(2) receptor subtype selectivity. The 5-HT(2A) receptor antagonism required a 2-min preincubation to attain maximum inhibition. 3. All PEAs tested shifted the 5-HT concentration-response curves to the right and downward. Their potencies varied with the nature of the C(4) substituent; the relative rank order of their 5-HT(2A) receptor antagonist potency was 2C-I>2C-B>2C-D>2C-H. 4. The present results demonstrate that in X. laevis oocytes, a series of 2,5-dimethoxy-4-substituted PEAs blocked the 5-HT(2A) but not the 5-HT(2C) receptor-mediated responses. As an alternative hypothesis, we suggest that the psychostimulant activity of the PEAs may not be exclusively associated with partial or full 5-HT(2A) receptor agonism.
Departamentos de Fisiología y, Instituto Milenio MIFAB, Centro de Regulación Celular y Patología Prof. J.V. Luco, Santiago, Chile. cvillalo@med.wayne.edu
Claudio A
CA
Villalobos
Paulina
P
Bull
Patricio
P
Sáez
Bruce K
BK
Cassels
J Pablo
JP
Huidobro-Toro
D000818:Animals; D003001:Cloning, Molecular; D004118:Dimethoxyphenylethylamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004336:Drug Antagonism; D008845:Microinjections; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D010627:Phenethylamines / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000008:administration & dosage / Q000235:genetics; D044405:Receptor, Serotonin, 5-HT2C / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification; D058830:Serotonin 5-HT2 Receptor Antagonists; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000378:metabolism*
D004118:Dimethoxyphenylethylamine; D010627:Phenethylamines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; C079321:2-(4-bromo-2,5-dimethoxyphenyl)ethylamine