Evaluation of isotryptamine derivatives at 5-HT2 serotonin receptors

On the basis that meta-chlorophenylpiperazine (mCPP; 1) is a nonselective 5-HT2C agonist, that benz-fused tryptamines (e.g., 5) display enhanced 5-HT2 affinity, and that certain isotryptamines 3 reportedly bind with enhanced affinity and selectivity at 5-HT2C receptors, we prepared and examined a series of isotryptamine-related analogues as potentially selective 5-HT2C agonists. None of the compounds displayed selectivity for 5-HT2C versus 5-HT2A receptors. Detailed re-examination of a compound previously reported to display 100-fold 5-HT2C selectivity [i.e., S(+)-5,6-difluoro-α-methylisotryptamine] revealed that its selectivity versus 5-HT2A receptors was, at best, only 10-fold.