5-HT1D SEROTONIN RECEPTORS - RESULTS OF A STRUCTURE-AFFINITY INVESTIGATION

As a prelude to the design of 5-HT1D agents, we systematically investigated the structure-affinity relationships for the binding of indolealkylamines and related derivatives at 5-HT1D serotonin receptors. The results of the investigation reveal that a) methylation of a 5-hydroxyl group decreases affinity by 2-fold, b) replacement of a 5-hydroxyl group by hydrogen reduces affinity by an order of magnitude, c) alpha-methylation of the side chain reduces affinity by approximately 50-fold, d) N,N-dimethylation decreases affinity by 4-fold, e) methylation at the 2-position reduces affinity by 300-fold, f) small alkyl substituents are not well tolerated at the C7- and N1-positions, g) shortening of the side chain by one methylene unit reduces affinity by two orders of magnitude, h) cyclization of the side chain to a beta-carboline dramatically reduces affinity, and i) the 5-hydroxy group can be replaced by a carboxamido, benzyloxy, or chlorobenzyloxy moiety without any decrease in affinity. These studies led to the evaluation of certain non-indolealkylamines and to the finding that a) simple phenylalkylamines and phenylpiperazines bind with low affinity, but that their benz-fused counterparts bind with significantly higher affinity, and b) the 7-methoxy analog of 1-(1-naphthyl)piperazine (7-OMe 1-NP) binds at 5-HT1D sites with an affinity (Ki = 2 nM) comparable to that of serotonin itself. Various leads were developed that might aid the subsequent design of 5-HT1D-selective agents.