Stereoselective LSD-like activity in a series of d-lysergic acid amides of (R)- 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 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.
Monte
A P
AP
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Marona-Lewicka
D
D
Kanthasamy
A
A
Sanders-Bush
E
E
Nichols
D E
DE
D016475:3T3 Cells; D000577:Amides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004193:Discrimination Learning / Q000187:drug effects; D008237:Lysergic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008238:Lysergic Acid Diethylamide / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D013237:Stereoisomerism
D000577:Amides; D011985:Receptors, Serotonin; D008238:Lysergic Acid Diethylamide; D008237:Lysergic Acid