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
Journal of Medicinal Chemistry – July 01, 1988
Source: OpenAlex
Summary
Optically pure alpha-methyltryptamines (AMTs) were successfully synthesized, showcasing a high degree of enantiomeric purity through a novel procedure involving 150 substituted indole-2-propanones. The affinity of these AMT enantiomers for serotonin receptors was tested, revealing that the S enantiomer exhibited higher binding affinity at the 5-HT2 receptor subtype when substituted with a 5-hydroxy or 5-methoxy group. Conversely, for 4-hydroxy or 4-methoxy substitutions, this trend reversed, highlighting the intricate relationship between stereochemistry and receptor interaction in neurotransmitter signaling.
Abstract
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.