137765-82-3

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 -(R)-DOI (-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) from rat cortical homogenate 5-HT2 receptors and in displacing -8-OH-DPAT (-8-hydroxy-2-(di-n-propylamino)tetralin) from rat hippocampal5-HT1A receptors.The difference in activity between the two isomeric amides was significant in both 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.