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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)203-211
Number of pages9
JournalJournal of Medicinal Chemistry
Volume35
Issue number2
DOIs
StatePublished - Jan 1 1992

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Lysergic Acid Diethylamide
Amides
8-Hydroxy-2-(di-n-propylamino)tetralin
Lysergic Acid
Serotonin 5-HT2 Receptor Agonists
Receptor, Serotonin, 5-HT1A
Mechanics
lysergamide

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Oberlender, Robert ; Pfaff, Robert C. ; Johnson, Michael P. ; Huang, Xuemei ; Nichols, David E. / Stereoselective LSD-like Activity in d-Lysergic Acid Amides of (R)- and (S)-2-Aminobutane. In: Journal of Medicinal Chemistry. 1992 ; Vol. 35, No. 2. pp. 203-211.
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Stereoselective LSD-like Activity in d-Lysergic Acid Amides of (R)- and (S)-2-Aminobutane. / Oberlender, Robert; Pfaff, Robert C.; Johnson, Michael P.; Huang, Xuemei; Nichols, David E.

In: Journal of Medicinal Chemistry, Vol. 35, No. 2, 01.01.1992, p. 203-211.

Research output: Contribution to journalArticle

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T1 - Stereoselective LSD-like Activity in d-Lysergic Acid Amides of (R)- and (S)-2-Aminobutane

AU - Oberlender, Robert

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N2 - 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.

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