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Titolo:
In vitro characterisation of the muscarinic receptor partial agonist, sabcomeline, in rat cortical and heart membranes
Autore:
Watson, JM; Hunter, AJ; Brown, AM; Middlemiss, DN;
Indirizzi:
SmithKline Beecham Pharmaceut, Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AW ssex, England
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACOLOGY
fascicolo: 1, volume: 370, anno: 1999,
pagine: 69 - 77
SICI:
0014-2999(19990401)370:1<69:IVCOTM>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACETYLCHOLINE-RECEPTOR; ALZHEIMERS-DISEASE; ADENYLATE-CYCLASE; FUNCTIONAL SELECTIVITY; CHOLINERGIC NEURONS; SMOOTH-MUSCLE; IN-VIVO; SUBTYPES; BRAIN; LOCALIZATION;
Keywords:
sabcomeline; cortex, rat; heart, rat; radioligand binding; [S-35]GTP gamma S binding; phosphoinositide hydrolysis; adenylyl cyclase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Middlemiss, DN SmithKlineW,eecham Pharmaceut, New Frontiers Sci Pk,3rd Ave, Harlow CM19 5A SmithKline Beecham Pharmaceut New Frontiers Sci Pk,3rd AveHarlow Essex England CM19 5AW
Citazione:
J.M. Watson et al., "In vitro characterisation of the muscarinic receptor partial agonist, sabcomeline, in rat cortical and heart membranes", EUR J PHARM, 370(1), 1999, pp. 69-77

Abstract

We have investigated the pharmacology of the functionally selective muscarinic M-1 receptor partial agonist, sabcomeline [SB-202026 (R-(Z)-(+)-alpha-(methoxyamino)-1-azabicyclo[2.2.2] octane-3-acetonitrile)], in rat cortex and heart using radioligand binding and functional studies. The Quinuclidinyl benzilate/Oxotremorine-M acetate ratio from radioligand binding studies suggested that sabcomeline and xanomeline [3(3-hexyloxy-1,25-thiadiazol-4-yl)- 1,2,5,6-tetrahydro-1-methylpyridine] are muscarinic receptor partial agonists in cortical and heart membranes. In [S-35]GTP gamma S binding studiesin rat cortex, carbachol stimulated binding via muscarinic M-2/M-4 receptors which could be blocked by sabcomeline with a pA(2) of 7.2. In rat heart membranes, carbachol also stimulated [S-35]GTP gamma S binding studies through muscarinic M-2 receptors. Sabcomeline caused a small stimulation of basal [S-35]GTP gamma S binding in both rat and heart tissues. Sabcomeline didnot stimulate phosphoinositide hydrolysis in rat cortical slices, but did block the muscarinic M-1 receptor-mediated response caused by carbachol with apparent pK(b) of 6.9. Xanomeline and milameline also had no effect on phosphoinositide hydrolysis up to 100 mu M In adenylyl cyclase studies in ratatria, sabcomeline inhibited forskolin-stimulated adenylyl cyclase activity to a similar extent to that of carbachol, xanomeline and milameline. The present study, using the techniques of radioligand binding, supports previous publications which have claimed that sabcomeline is a muscarinic receptor partial agonist. As expected, this study shows that the functional actions of this compound at muscarinic receptor subtypes and in different tissueswill depend on receptor reserve. (C) 1999 Elsevier Science B.V. All rightsreserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/10/20 alle ore 22:56:43