Lysergamides of Isomeric 2,4-Dimethylazetidines Map the Binding Orientation of the Diethylamide Moiety in the Potent Hallucinogenic Agent N,N-Diethyllysergamide (LSD)
| Autor: | David E. Nichols, Stewart Frescas, Deborah M. Kurrasch-Orbaugh, Danuta Marona-Lewicka |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
Models Molecular Lysergamides Stereochemistry medicine.drug_class Azetidine Drug Evaluation Preclinical Molecular Conformation Stereoisomerism Carboxamide Crystallography X-Ray Binding Competitive Discrimination Learning Rats Sprague-Dawley Mice Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Receptor Serotonin 5-HT2C medicine Animals Moiety Receptor Serotonin 5-HT2A Diethylamine Diastereomer 3T3 Cells Rats Lysergic acid Lysergic Acid Diethylamide chemistry Receptors Serotonin Hallucinogens Azetidines Molecular Medicine Receptors Serotonin 5-HT1 medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 45:4344-4349 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm020153s |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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