title: Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD).
abstract: Lysergic acid amides were prepared from (R,R)-(-)-, (S,S)-(+)-, and cis-2,4-dimethyl azetidine. The dimethylazetidine moiety is considered here to be a rigid analogue of diethylamine, and thus, the target compounds are all conformationally constrained analogues of the potent hallucinogenic agent, N,N-diethyllysergamide, LSD-25. Pharmacological evaluation showed that (S,S)-(+)-2,4-dimethylazetidine gave a lysergamide with the highest LSD-like behavioral activity in the rat two lever drug discrimination model that was slightly more potent than LSD itself. This same diastereomer also had the highest affinity and functional potency at the rat serotonin 5-HT(2A) receptor, the presumed target for hallucinogenic agents, and a receptor affinity profile in a panel of screens that was most similar to that of LSD itself. Both cis- and the (R,R)-trans-dimethylazetidines gave lysergamides that were less potent in all relevant assays. The finding that the S,S-dimethylazetidine gave a lysergamide with pharmacology most similar to LSD indicates that the N,N-diethyl groups of LSD optimally bind when they are oriented in a conformation distinct from that observed in the solid state by X-ray crystallography. The incorporation of isomeric dialkylazetidines into other biologically active molecules may be a useful strategy to model the active conformations of dialkylamines and dialkylamides.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA. drdave@pharmacy.purdue.edu
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.forename: Stewart
authors.initials: S
authors.lastname: Frescas
authors.forename: Danuta
authors.initials: D
authors.lastname: Marona-Lewicka
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Kurrasch-Orbaugh
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004193:Discrimination Learning / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006213:Hallucinogens / Q000737:chemistry* / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C465782:2,4-dimethylazetidine; D001384:Azetidines; D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D008238:Lysergic Acid Diethylamide