Binding of Indolylalkylamines at 5-HT2 Serotonin Receptors: Examination of a Hydrophobic Binding Region

Article abstract of DOI:10.1021/jm00172a016

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 α-methyltryptamine in order to improve its affinity and selectivity.It was determined that substitution of an n-propyl or amyl group has similar effect on affinity regardless of location (i.e., N1 or C7).The low affinity of several N1-alkylpyrroleethylamines suggests that the benzene portion of the α-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-α-methyltryptamine (3h) binds with significant affinity (Ki = 12 nM) and selectivity at 5-HT2 receptors relative to 5-HT_1A (Ki = 7100 nM), 5-HT_1B (Ki = 5000 nM), 5-HT_1C (Ki = 120 nM), and 5-HT_1D (Ki > 10000 nM) receptors.As a consequence, this is the most 5-HT2-selective indolylalkylamine derivative reported to date.