Stereoselective LSD-like activity in d-lysergic acid amides of R- and S-2-aminobutane
Robert Oberlender, Robert C. Pfaff, Michael P. Johnson, Xuemei Huang, David E. Nichols
Journal of Medicinal Chemistry 1992 DOI: 10.1021/jm00080a001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Measures | drug discrimination, receptor binding assays |
| Topics | LSD |
| Keywords | Stereochemistry Agonist Substituent Receptor Carboxamide Stereoselectivity Biological activity |
| Citations | 17 |
| Key findings | The (R)-2-butylamide of d-lysergic acid is more potent than the (S)-isomer in behavioral and binding assays, and its conformation resembles LSD, indicating stereochemistry of the amide substituent critically influences activity. |
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.