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Synthesis and serotonin receptor affinities of a series of enantiomers of alpha-methyltryptamines: evidence for the binding conformation of tryptamines at serotonin 5-HT1B receptors.

A procedure for the preparation of optically pure alpha-methyltryptamines (AMTs) from substituted indoles was developed. The key step in the sequence was the reductive amination of substituted indole-2-propanones with the commercially available pure enantiomers of alpha-methylbenzylamine, followed by the chromatographic separation of the resulting pair of diastereomeric amines by preparative centrifugal (Chromatotron) chromatography. Catalytic N-debenzylation then afforded the pure AMT enantiomers. Optical purity was established by chiral HPLC analysis of the 2-naphthoylamide derivatives. An improved procedure for the preparation of indole-2-propanones was also developed. To probe structure-activity relationships of serotonin receptors, affinities of the alpha-methyltryptamine enantiomers were then measured at the 5-HT2 antagonist receptor subtype, with displacement of [3H]ketanserin, and were estimated at the 5-HT1B receptor, with displacement of [3H]serotonin, respectively, in rat frontal cortex homogenates. Enantioselectivity at the receptor subtypes varied, depending on aromatic substituents. For a 5-hydroxy or 5-methoxy, the S enantiomer had higher affinity or was equipotent to the R enantiomer. This selectivity at [3H]serotonin binding sites was reversed for 4-oxygenated alpha-methyltryptamines, where a 4-hydroxy or 4-methoxy did not enhance affinity over the unsubstituted compounds. These results can be explained, for the [3H]serotonin displacement data, if the binding conformation is one where the ethylamine side chain is trans and lying in a plane perpendicular to the indole ring plane.