Four cyclic analogues of the psychoactive compound MDA were tested in rats trained to discriminate either LSD or MDMA from saline. None of the methylenedioxy compounds caused LSD-like effects, but two of them (3a and 3b) fully substituted for MDMA, indicating similar acute behavioral effects. However, unlike MDA, neither 3a nor 3b reduced serotonin or its metabolite levels in the cortex or hippocampus, nor did they decrease serotonin transporter binding sites after a single 40 mg/kg dose. These results suggest that 3a and 3b share MDMA-like acute behavioral properties but lack the serotonin neurotoxicity associated with MDA.
A new method produces pure mirror-image forms of alpha-methyltryptamines (AMTs) from substituted indoles. The key step uses reductive amination with pure enantiomers of alpha-methylbenzylamine, followed by chromatographic separation and catalytic N-debenzylation. Optical purity was confirmed by chiral HPLC. Affinities of the AMT enantiomers were measured at 5-HT2 and 5-HT1B serotonin receptor subtypes in rat frontal cortex homogenates. Enantioselectivity depended on aromatic substituents: for 5-hydroxy or 5-methoxy, the S enantiomer had higher or equal affinity compared to the R enantiomer. For 4-oxygenated AMTs, this selectivity reversed, and 4-hydroxy or 4-methoxy did not improve affinity over unsubstituted compounds. The results suggest a binding conformation where the ethylamine side chain is trans and perpendicular to the indole ring plane.
Both the (R)- and (S)-2-butylamides of d-lysergic acid fully substituted for LSD in rats trained to discriminate LSD from saline, and both showed very high affinity for 5-HT2 and 5-HT1A receptors. The R isomer was significantly more potent than the S isomer in both behavioral and binding assays. Molecular mechanics modeling indicated that the (R)-2-butylamide adopts a conformation similar to LSD, whereas the (S)-2-butylamide does not. These results suggest that the stereochemistry of the amide substituent critically influences hallucinogenic activity, possibly through stereoselective interactions with a hydrophobic receptor region or by inducing conformational changes elsewhere in the molecule.