Binding of indolylalkylamines at 5-HT2 serotonin receptors: examination of a hydrophobic binding region

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Abstract
Taking advantage of a proposed hydrophobic region on 5-HT2 receptors previously identified by radioligand-binding studies utilizing various phenylisopropylamine derivatives, we prepared and evaluated several N1- and/or C7-alkyl-substituted derivatives of .alpha.-methyltryptamine in order to improve its affinity and selectivity. It was determined that substitution of an n-propyl or amyl group has similar efect on affinity regardless of location (i.e., N1 or C7). The low affinity of several N1-alkylpyrroleethylamines suggests that the benzene portion of the .alpha.-methyltryptamines is necessary for significant affinity. Whereas tryptamine derivatives generally display little selectivity for the various populations of 5-HT receptors, N1-n-propyl-5-methoxy-.alpha.-methyltryptamine (3h) binds with significant affinity (Ki = 12 nM) and selectivity at 5HT2 receptors relative to 5-HT1A (Ki = 7100 nM), 5-HT1B (Ki = 5000 nM), 5-HT1C (Ki = 120 nM), and 5-HT1D (Ki > 10,000 nM) receptors. As a consequence, this is the most 5-HT2-selective indolylalkylamine derivative reported to date.