Stereoselective LSD-like activity in d-lysergic acid amides of (R)- and (S)-2-aminobutane

The (R)- and (S)-2-butylamides of d-lysergic acid were prepared and evaluated in behavioral and biochemical assays of 5-HT2 agonist activity. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, both isomers completely substituted for the training stimulus. Similarly, both isomers we...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1992-01, Vol.35 (2), p.203-211
Main Authors: OBERLENDER, R, PFAFF, R. C, JOHNSON, M. P, XUEMEI HUANG, NICHOLS, D. E
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Biological and medical sciences
Discrimination (Psychology)
Hallucinogens - chemical synthesis
Hallucinogens - metabolism
Hallucinogens - pharmacology
In Vitro Techniques
Lysergic Acid Diethylamide - analogs & derivatives
Lysergic Acid Diethylamide - chemical synthesis
Lysergic Acid Diethylamide - metabolism
Lysergic Acid Diethylamide - pharmacology
Male
Medical sciences
Models, Molecular
Molecular Conformation
Neuropharmacology
Pharmacology. Drug treatments
Psychodysleptics: hallucinogen
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Radioligand Assay
Rats
Rats, Inbred Strains
Receptors, Serotonin - metabolism
Stereoisomerism
Structure-Activity Relationship
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The (R)- and (S)-2-butylamides of d-lysergic acid were prepared and evaluated in behavioral and biochemical assays of 5-HT2 agonist activity. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, both isomers completely substituted for the training stimulus. Similarly, both isomers were found to possess very high affinity in displacing [125I]-(R)-DOI ([125I]-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane) from rat cortical homogenate 5-HT2 receptors and in displacing [3H]-8-OH-DPAT ([3H]-8-hydroxy-2-(di-n-propylamino)tetralin) from rat hippocampal 5-HT1A receptors. The difference in activity between the two isomeric amides was significant in both the behavioral and binding assays, with the R isomer possessing greater potency. Molecular mechanics were used to predict the active geometries of the subject compounds. It was found that the (R)-2-butylamide has a conformation quite similar to LSD, while the (S)-2-butylamide does not. These results suggest that stereochemical properties of the amide substituent of hallucinogenic lysergamides may exert a critical influence on activity. It is concluded that the conformation of the amide function may directly affect binding through stereoselective interactions with a hydrophobic region on the receptor, indirectly by inducing conformational changes elsewhere in the molecule, or by a combination of these two mechanisms.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00080a001