The 3-pentyl-, (R)- and (S)-2-pentyl-, 2-hexyl-, and 2-heptylamides of d-lysergic acid were synthesized and evaluated in biochemical and behavioral assays for LSD-like activity. In radioligand competition studies, the (R)-lysergamides were consistently more potent than the (S)-amides in displacing [3H]ketanserin from 5-HT2A receptors in rat cortical homogenate and in displacing [3H]-8-OH-DPAT ([3H]-8-hydroxy-2-(di-n- propylamino)tetralin) from rat hippocampal 5-HT1A receptors. As the amide alkyl was lengthened from pentyl to heptyl, the affinity of the (R)-isomers for 5-HT2A sites decreased, while affinity for 5-HT1A sites was maximal for the (R)-2-hexyllysergamide. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, a similar stereoselective effect was noted in which the (R)-alkylamides were more potent than the (S)-isomers in producing the LSD-like discriminative stimulus effect. However, as the amide alkyl substituent was increased in length, LSD-like activity decreased, with only partial substitution for training drug being observed for the (R)-hexylamide. The (R)- and (S)-pentyllysergamides were also assayed for their ability to activate intracellular phosphoinositide hydrolysis. Consistent with the binding and behavioral studies, these assays showed that both isomers are potent agonists at the 5-HT2A receptor, but that the (R)-pentyllysergamide is approximately 20 times more active than the (S)-pentyllysergamide in stimulating phosphoinositide turnover.