A POTENT NEW CLASS OF KAPPA-RECEPTOR AGONIST - 4-SUBSTITUTED 1-(ARYLACETYL)-2-[(DIALKYLAMINO)METHYL]PIPERAZINES

被引：84
|
作者：
NAYLOR, A [1 ]
JUDD, DB [1 ]
LLOYD, JE [1 ]
SCOPES, DIC [1 ]
HAYES, AG [1 ]
BIRCH, PJ [1 ]
机构：
[1] GLAXO GRP RES LTD,DEPT NEUROPHARMACOL,WARE SG12 0DJ,HERTS,ENGLAND
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 1993年 / 36卷 / 15期
关键词：
D O I：
10.1021/jm00067a004
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxy late (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10 000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10 000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal
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页码：2075 / 2083
页数：9
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