5‐HT1D serotonin receptors: Results of a structure‐affinity investigation

As a prelude to the design of 5‐HT 1D agents, we systematically investigated the structure‐affinity relationships for the binding of indolealkylamines and related derivatives at 5‐HT 1D 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) α‐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 β‐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 benzfused counterparts bind with significantly higher affinity, and (b) the 7‐methoxy analog of 1‐(1‐naphthyl)piperazine (7‐OMe 1‐NP) binds at 5‐HT 1D 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‐HT 1D ‐selective agents.