STEREOSELECTIVE LSD-LIKE ACTIVITY IN D-LYSERGIC-ACID AMIDES OF (R)-2-AMINOBUTANE AND (S)-2-AMINOBUTANE

被引:16
作者
OBERLENDER, R
PFAFF, RC
JOHNSON, MP
HUANG, XM
NICHOLS, DE
机构
[1] PURDUE UNIV,SCH PHARM & PHARMACAL SCI,DEPT MED CHEM & PHARMACOGNOSY,W LAFAYETTE,IN 47907
[2] PURDUE UNIV,SCH PHARM & PHARMACAL SCI,DEPT PHARMACOL & TOXICOL,W LAFAYETTE,IN 47907
关键词
D O I
10.1021/jm00080a001
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 [I-125]-(R)-DOI ([I-125]-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) from rat cortical homogenate 5-HT2 receptors and in displacing [H-3]-8-OH-DPAT ([H-3]-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 lysergamide 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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页码:203 / 211
页数:9
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