Stereoselective LSD-like Activity in a Series of d-Lysergic Acid Amides of (R)- and (S)-2-Aminoalkanes
Aaron Monte, Danuta Marona‐lewicka, Arthi Kanthasamy, Elaine Sanders‐bush, David E. Nichols
Journal of Medicinal Chemistry March 1, 1995 DOI: 10.1021/jm00006a015 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat cortical homogenate, rat hippocampal tissue, and rats trained to discriminate LSD |
| Topics | LSD |
| Keywords | Stereochemistry Stereoselectivity Carboxamide Receptor Substituent Phenethylamine |
| Citations | 25 |
| Key findings | (R)-lysergamides showed consistently higher potency than (S)-amides in binding to 5-HT2A and 5-HT1A receptors and in producing LSD-like behavioral effects, with (R)-pentyllysergamide being about 20 times more active than the (S)-isomer in stimulating phosphoinositide hydrolysis. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 16
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- 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
- Lysergamides of Isomeric 2,4-Dimethylazetidines Map the Binding Orientation of the Diethylamide Moiety in the Potent Hallucinogenic Agent N,N-Diethyllysergamide (LSD) Journal of Medicinal Chemistry September 1, 2002
and 11 more in the library
Cites 17
- Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. Journal of Pharmacology and Experimental Therapeutics September 1, 1988
- How LSD Originated Journal of Psychedelic Drugs 1979
- Neuropharmacological reassessment of the discriminative stimulus properties ofd-lysergic acid diethylamide (LSD) Psychopharmacology 1987
- Pharmacology of Lysergic Acid Diethylamide and Some of Its Related CompoundS Journal of Pharmacy and Pharmacology September 1, 1957
- Characterization of the Discriminative Stimulus Properties Induced by 5‐HT1and 5‐HT2Agonists in Rats Pharmacology & Toxicology February 1, 1989
and 12 more in the library