Evaluation of isotryptamine derivatives at 5-HT(2) serotonin receptors.

On the basis that meta-chlorophenylpiperazine (mCPP; 1) is a nonselective 5-HT(2C) agonist, that benz-fused tryptamines (e.g., 5) display enhanced 5-HT(2) affinity, and that certain isotryptamines 3 reportedly bind with enhanced affinity and selectivity at 5-HT(2C) receptors, we prepared and examined a series of isotryptamine-related analogues as potentially selective 5-HT(2C) agonists. None of the compounds displayed selectivity for 5-HT(2C) versus 5-HT(2A) receptors. Detailed re-examination of a compound previously reported to display 100-fold 5-HT(2C) selectivity [i.e., S(+)-5,6-difluoro-alpha-methylisotryptamine] revealed that its selectivity versus 5-HT(2A) receptors was, at best, only 10-fold.