Stereoselective LSD-like Activity in D-Lysergic Acid Amides of (R)- And (S)-2-aminobutane

J Med Chem. 1992 Jan 24;35(2):203-11. doi: 10.1021/jm00080a001.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Discrimination, Psychological
  • 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
  • Models, Molecular
  • Molecular Conformation
  • Radioligand Assay
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Hallucinogens
  • Receptors, Serotonin
  • 2-butyllysergamide
  • Lysergic Acid Diethylamide