title: Stereoselective LSD-like activity in d-lysergic acid amides of (R)- and (S)-2-aminobutane.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: R
authors.initials: R
authors.lastname: Oberlender
authors.forename: R C
authors.initials: RC
authors.lastname: Pfaff
authors.forename: M P
authors.initials: MP
authors.lastname: Johnson
authors.forename: X M
authors.initials: XM
authors.lastname: Huang
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D004192:Discrimination, Psychological; D006213:Hallucinogens / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008238:Lysergic Acid Diethylamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006213:Hallucinogens; D011985:Receptors, Serotonin; C072399:2-butyllysergamide; D008238:Lysergic Acid Diethylamide