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

引用

页码：2075 / 2083

页数：9

共 23 条

[11] ENDOGENOUS OPIOID PEPTIDES - MULTIPLE AGONISTS AND RECEPTORS [J].

LORD, JAH ;

WATERFIELD, AA ;

HUGHES, J ;

KOSTERLITZ, HW .

NATURE, 1977, 267 (5611) :495-499

[12]

MARTIN WR, 1976, J PHARMACOL EXP THER, V197, P517

[13]

Martin WR, 1984, PHARMACOL REV, V35, P283

[14] KAPPA-OPIOID RECEPTORS AND ANALGESIA [J].

MILLAN, MJ .

TRENDS IN PHARMACOLOGICAL SCIENCES, 1990, 11 (02) :70-76

[15] RABBIT VAS-DEFERENS - A SPECIFIC BIOASSAY FOR OPIOID KAPPA-RECEPTOR AGONISTS [J].

OKA, T ;

NEGISHI, K ;

SUDA, M ;

MATSUMIYA, T ;

INAZU, T ;

UEKI, M .

EUROPEAN JOURNAL OF PHARMACOLOGY, 1981, 73 (2-3) :235-236

[16] CLASSIFICATION OF OPIOID RECEPTORS [J].

PATERSON, SJ ;

ROBSON, LE ;

KOSTERLITZ, HW .

BRITISH MEDICAL BULLETIN, 1983, 39 (01) :31-36

[17]

PERRIN DD, 1980, PURIFICATION LABORAT

[18]

Rees D C, 1992, Prog Med Chem, V29, P109, DOI 10.1016/S0079-6468(08)70006-7

[19] NEW KAPPA-RECEPTOR AGONISTS BASED UPON A 2-((ALKYLAMINO)METHYL)PIPERIDINE NUCLEUS [J].

SCOPES, DIC ;

HAYES, NF ;

BAYS, DE ;

BELTON, D ;

BRAIN, J ;

BROWN, DS ;

JUDD, DB ;

MCELROY, AB ;

MEERHOLZ, CA ;

NAYLOR, A ;

HAYES, AG ;

SHEEHAN, MJ ;

BIRCH, PJ ;

TYERS, MB .

JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (03) :490-501

[20] OPIATE RECEPTORS IN THE RAT VAS-DEFERENS [J].

SMITH, CFC ;

RANCE, MJ .

LIFE SCIENCES, 1983, 33 :327-330

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