STEREOSELECTIVE LSD-LIKE ACTIVITY IN A SERIES OF D-LYSERGIC-ACID AMIDES OF (R)-2-AMINOALKANES AND (S)-2-AMINOALKANES

The 3-pentyl-, (R)- and (S)-2-pentyl-, 2-hexyl-, and 2-heptylamides of d-lysergic acid were synthesized and evaluated in biochemical and beh avioral assays for LSD-like activity. In radioligand competition studi es, the (R)-lysergamides were consistently more potent than the (S)-am ides in displacing [H-3]ketanserin from 5-HT2A receptors in rat cortic al homogenate and in displacing [H-3]-8-OH-DPAT ([H-3]-8-hydroxy-2-(di -n-propylamino)tetralin) from. rat hippocampal 5-HT1A receptors. As th e amide alkyl was lengthened from pentyl to heptyl, the affinity of th e (R)-isomers for 5-HT2A sites decreased, while affinity for 5-HT1A si tes was maximal for the (R)-2-hexyllysergamide. In rats trained to dis criminate 0.08 mg/kg LSD tartrate from saline, a similar stereoselecti ve effect was noted in which the (R)-alkylamides were more]potent than the (S)-isomers in producing the LSD-like discriminative stimulus eff ect. However, as the amide alkyl substituent was increased in length, LSD-like activity decreased, with only partial substitution for traini ng drug being observed for the (R)-hexylamide. The (R)- and (S)-pentyl lysergamides were also assayed for their ability to activate intracell ular phosphoinositide hydrolysis. Consistent with the binding and beha vioral studies, these assays showed that both isomers are potent agoni sts at the 5-HT2A receptor, but that the (R)-pentyllysergamide is appr oximately 20 times more active than the (S)-pentyllysergamide in stimu lating phosphoinositide turnover.