NEW KAPPA-RECEPTOR AGONISTS BASED UPON A 2-((ALKYLAMINO)METHYL)PIPERIDINE NUCLEUS

被引：29

作者：

SCOPES, DIC ^{[1
]}

HAYES, NF ^{[1
]}

BAYS, DE ^{[1
]}

BELTON, D ^{[1
]}

BRAIN, J ^{[1
]}

BROWN, DS ^{[1
]}

JUDD, DB ^{[1
]}

MCELROY, AB ^{[1
]}

MEERHOLZ, CA ^{[1
]}

NAYLOR, A ^{[1
]}

HAYES, AG ^{[1
]}

SHEEHAN, MJ ^{[1
]}

BIRCH, PJ ^{[1
]}

TYERS, MB ^{[1
]}

机构：

[1] GLAXO GRP RES LTD,DEPT NEUROPHARMACOL,WARE SG12 0DP,HERTS,ENGLAND

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1992年 / 35卷 / 03期

关键词：

D O I：

10.1021/jm00081a009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]2-[(alkylamino)methyl]peperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]2-[[1-(3-oxopyrrolidinyl)methyl]?? piperidine (10) possesses high activity in the rabbit vas deferens (LCD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antiociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg sc). The spirocyclic analogue 8-[3,4-dichlorophenyl)acetyl]7-(1-pyrrolidinylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.

引用

页码：490 / 501

页数：12

共 27 条

[11]

HAYES AG, 1987, J PHARMACOL EXP THER, V240, P984

[12] DIISOBUTYLALUMINUM "2,6-DI-TERT-BUTYL-4-METHYLPHENOXIDE - NOVEL STEREOSELECTIVE REDUCING AGENT FOR PROSTAGLANDIN SYNTHESIS [J].

IGUCHI, S ;

NAKAI, H ;

HAYASHI, M ;

YAMAMOTO, H ;

MARUOKA, K .

BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, 1981, 54 (10) :3033-3041

[13]

JUNG ME, 1981, TETRAHEDRON LETT, V22, P4607, DOI 10.1016/S0040-4039(01)82993-2

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

LORD, JAH ;

WATERFIELD, AA ;

HUGHES, J ;

KOSTERLITZ, HW .

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

[15]

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

[16]

Martin WR, 1984, PHARMACOL REV, V35, P283

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

MILLAN, MJ .

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

[18]

OJIMA I, 1972, TETRAHEDRON LETT, P5035

[19] 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

[20]

PERRIN DD, 1980, PURIFICATION LABORAT

← 1 2 3 →