4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A 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‐CH3=2C‐D analogs, are partial agonists at 5‐HT2C receptors, and show low or even negligible intrinsic efficacy at 5‐HT2A receptors. These results raised the proposal that these drugs may act as 5‐HT2 antagonists. To test this hypothesis, Xenopus laevis oocytes were microinjected with the rat clones for 5‐HT2A or 5‐HT2C receptors. The above‐mentioned PEAs and its 4‐H analog (2C‐H) blocked the 5‐HT‐induced currents at 5‐HT2A, but not at the 5‐HT2C receptor, revealing 5‐HT2 receptor subtype selectivity. The 5‐HT2A 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‐HT2A 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‐HT2A but not the 5‐HT2C 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‐HT2A receptor agonism. British Journal of Pharmacology (2004) 141, 1167–1174. doi:10.1038/sj.bjp.0705722