Stereoselective LSD-like activity in d-lysergic acid amides of R- and S-2-aminobutane
Journal of Medicinal Chemistry – January 01, 1992
Source: OpenAlex
Summary
The (R)-2-butylamide of d-lysergic acid demonstrated significantly greater potency than its (S) counterpart in behavioral and biochemical assays, with both isomers fully substituting for LSD in rats. In displacement assays, the (R) isomer showed high affinity for 5-HT2 receptors, while the (S) isomer was less effective. Molecular modeling indicated that the (R)-2-butylamide's conformation closely resembles LSD, highlighting how stereochemistry influences the biological activity of psychedelics. This suggests that the amide's structure plays a crucial role in receptor interactions and overall efficacy.
Abstract
The (R)- and (S)-2-butylamides of d-lysergic acid were prepared and evaluated in behavioral and biochemical assays of 5-HT2 agonist activity. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, both isomers completely substituted for the training stimulus. Similarly, both isomers were found to possess very high affinity in displacing [125I]-(R)-DOI ([125I]-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane) from rat cortical homogenate 5-HT2 receptors and in displacing [3H]-8-OH-DPAT ([3H]-8-hydroxy-2-(di-n-propylamino)tetralin) from rat hippocampal 5-HT1A receptors. The difference in activity between the two isomeric amides was significant in both the behavioral and binding assays, with the R isomer possessing greater potency. Molecular mechanics were used to predict the active geometries of the subject compounds. It was found that the (R)-2-butylamide has a conformation quite similar to LSD, while the (S)-2-butylamide does not. These results suggest that stereochemical properties of the amide substituent of hallucinogenic lysergamides may exert a critical influence on activity. It is concluded that the conformation of the amide function may directly affect binding through stereoselective interactions with a hydrophobic region on the receptor, indirectly by inducing conformational changes elsewhere in the molecule, or by a combination of these two mechanisms.