2-(3,4-DICHLOROPHENYL)-N-METHYL-N-[2-(1-PYRROLIDINYL)-1-SUBSTITUTED-ETHYL]-ACETAMIDES - THE USE OF CONFORMATIONAL-ANALYSIS IN THE DEVELOPMENT OF A NOVEL SERIES OF POTENT OPIOID KAPPA-AGONISTS

被引:72
作者
COSTELLO, GF [1 ]
JAMES, R [1 ]
SHAW, JS [1 ]
SLATER, AM [1 ]
STUTCHBURY, NCJ [1 ]
机构
[1] ICI PLC PHARMACEUT,RES DEPT,ALDERLEY PK,MACCLESFIELD SK10 4TG,CHESHIRE,ENGLAND
关键词
D O I
10.1021/jm00105a027
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides (1), methylated at C1 and/or C2 of the ethyl linking group, and their biological evaluation as opioid kappa-agonists. Conformational analysis of corresponding desaryl analogues 2 suggested that only those compounds capable of occupying an energy minimum close to that of the known kappa-agonist N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide U-50488 might posses kappa-agonist properties. Starting from chiral amino acids, other alkyl and aryl substituents were introduced at C1 of the ethyl-linking moiety, giving compounds capable of adopting the same conformation as U-50488. The most potent of these, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl]acetamide (8), was 146-fold more active than U-50488 in vitro in the mouse vas deferens model and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.004 mg/kg sc) in an abdominal constriction model.
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页码:181 / 189
页数:9
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