4‐Bromo‐2,5‐dimethoxyphenethylamine (2C‐B) and structurally related phenylethylamines are potent 5‐HT 2A receptor antagonists in Xenopus laevis oocytes

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. 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. 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. 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.British Journal of Pharmacology (2004) 141 , 1167–1174. doi: 10.1038/sj.bjp.0705722