Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors

被引：122

作者：

Holladay, MW ^{[1
]}

Wasicak, JT ^{[1
]}

Lin, NH ^{[1
]}

He, Y ^{[1
]}

Ryther, KB ^{[1
]}

Bannon, AW ^{[1
]}

Buckley, MJ ^{[1
]}

Kim, DJB ^{[1
]}

Decker, MW ^{[1
]}

Anderson, DJ ^{[1
]}

Campbell, JE ^{[1
]}

Kuntzweiler, TA ^{[1
]}

Donnelly-Roberts, DL ^{[1
]}

Piattoni-Kaplan, M ^{[1
]}

Briggs, CA ^{[1
]}

Williams, M ^{[1
]}

Arneric, SP ^{[1
]}

机构：

[1] Abbott Labs, Neurol & Urol Dis Res D47W, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 04期

关键词：

D O I：

10.1021/jm9706224

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (ip) or oral (po) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

引用

页码：407 / 412

页数：6

共 31 条

[21] THE HEALTH CONSEQUENCES OF SMOKING - CARDIOVASCULAR-DISEASES [J].

MCBRIDE, PE .

MEDICAL CLINICS OF NORTH AMERICA, 1992, 76 (02) :333-353

[22]

PABREZA LA, 1990, MOL PHARMACOL, V39, P9

[23]

QIAN CG, 1993, EUR J PHARMACOL, V250, pR13

[24] Evaluation of anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands in the rat tail-flick assay [J].

Rao, TS ;

Correa, LD ;

Reid, RT ;

Lloyd, GK .

NEUROPHARMACOLOGY, 1996, 35 (04) :393-405

[25] EPIBATIDINE - A NOVEL (CHLOROPYRIDYL)AZABICYCLOHEPTANE WITH POTENT ANALGESIC ACTIVITY FROM AN ECUADORIAN POISON FROG [J].

SPANDE, TF ;

GARRAFFO, HM ;

EDWARDS, MW ;

YEH, HJC ;

PANNELL, L ;

DALY, JW .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1992, 114 (09) :3475-3478

[26]

SULLIVAN JP, 1994, J PHARMACOL EXP THER, V271, P624

[27] A-85380 [3-(2(S)-azetidinylmethoxy)pyridine]: In vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand [J].

Sullivan, JP ;

DonnellyRoberts, D ;

Briggs, CA ;

Anderson, DJ ;

Gopalakrishnan, M ;

PiattoniKaplan, M ;

Campbell, JE ;

McKenna, DG ;

Molinari, E ;

Hettinger, AM ;

Garvey, DS ;

Wasicak, JT ;

Holladay, MW ;

Williams, M ;

Arneric, SP .

NEUROPHARMACOLOGY, 1996, 35 (06) :725-734

[28]

Sullivan JP, 1997, J PHARMACOL EXP THER, V283, P235

[29]

SULLIVAN JP, 1996, CNS DRUG REV, V2, P21

[30]

SULLIVAN JP, 1994, MED CHEM RES, V4, P502

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