Lysergamides of Isomeric 2,4-Dimethylazetidines Map the Binding Orientation of the Diethylamide Moiety in the Potent Hallucinogenic Agent N,N-Diethyllysergamide (LSD)
David E. Nichols, Stewart Frescas, Danuta Marona‐lewicka, Deborah Kurrasch‐orbaugh
Journal of Medicinal Chemistry September 1, 2002 DOI: 10.1021/jm020153s (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | R)-(-)- (S S)-(+)- and cis-2 4-dimethylazetidine |
| Topics | LSD |
| Keywords | Hallucinogen Moiety Stereochemistry Biological activity Diastereomer Structure–activity relationship Diethylamine Receptor |
| Citations | 89 |
| Key findings | The (S,S)-(+)-2,4-dimethylazetidine lysergamide was slightly more potent than LSD in a rat drug discrimination model and had the highest affinity and functional potency at the serotonin 5-HT(2A) receptor, indicating that the N,N-diethyl groups of LSD bind in a conformation distinct from that observed in the solid state. |
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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 50
- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
- The Pharmacology of Lysergic Acid Diethylamide: A Review CNS Neuroscience & Therapeutics November 11, 2008
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- Psychedelics and the Human Receptorome PLoS One 2010
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Cites 11
- Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines Journal of Medicinal Chemistry October 19, 2000
- Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups Journal of Medicinal Chemistry 1996
- Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists Journal of Medicinal Chemistry January 26, 2001
- Stereoselective LSD-like Activity in a Series of d-Lysergic Acid Amides of (R)- and (S)-2-Aminoalkanes Journal of Medicinal Chemistry March 1, 1995
- Molecular Structure of LSD Science November 10, 1972
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