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Titolo:
MUSCARINIC ANALGESICS WITH POTENT AND SELECTIVE EFFECTS ON THE GASTROINTESTINAL-TRACT - POTENTIAL APPLICATION FOR THE TREATMENT OF IRRITABLE-BOWEL-SYNDROME
Autore:
MITCH CH; BROWN TJ; BYMASTER FP; CALLIGARO DO; DIECKMAN D; MERRIT L; PETERS SC; QUIMBY SJ; SHANNON HE; SHIPLEY LA; WARD JS; HANSEN K; OLESEN PH; SAUERBERG P; SHEARDOWN MJ; SWEDBERG MDB; SUZDAK P; GREENWOOD B;
Indirizzi:
ELI LILLY & CO,LILLY RES LABS,LILLY CORP,NEUROSCI BRANCH INDIANAPOLISIN 46285 NOVO NORDISK AS,HLTH CARE DISCOVERY MALOV DENMARK
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 4, volume: 40, anno: 1997,
pagine: 538 - 546
SICI:
0022-2623(1997)40:4<538:MAWPAS>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANESTHETIZED FERRET; NERVOUS-SYSTEM; AGONISTS; MOTILITY; RECEPTOR; IDENTIFICATION; DERIVATIVES; DIFFERENCE; TRANSPORT; JEJUNUM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
36
Recensione:
Indirizzi per estratti:
Citazione:
C.H. Mitch et al., "MUSCARINIC ANALGESICS WITH POTENT AND SELECTIVE EFFECTS ON THE GASTROINTESTINAL-TRACT - POTENTIAL APPLICATION FOR THE TREATMENT OF IRRITABLE-BOWEL-SYNDROME", Journal of medicinal chemistry, 40(4), 1997, pp. 538-546

Abstract

Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-basedstructures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. ]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED(50) = 0.1 mg/kg) along with potency for normalization of GI motility (ED(50) = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.

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Documento generato il 01/10/20 alle ore 00:53:13