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Titolo:
In vitro and in vivo m2 muscarinic subtype selectivity of some dibenzodiazepinones and pyridobenzodiazepinones
Autore:
Cohen, VI; Jin, BY; McRee, RC; Boulay, SF; Cohen, EI; Sood, VK; Zeeberg, BR; Reba, RC;
Indirizzi:
George Washington Univ, Med Ctr, Sect Radiopharmaceut Chem, Washington, DC20037 USA George Washington Univ Washington DC USA 20037 m, Washington, DC20037 USA Univ Chicago, Dept Radiol, Nucl Med Sect, Chicago, IL 60637 USA Univ Chicago Chicago IL USA 60637 l, Nucl Med Sect, Chicago, IL 60637 USA
Titolo Testata:
BRAIN RESEARCH
fascicolo: 2, volume: 861, anno: 2000,
pagine: 305 - 315
SICI:
0006-8993(20000410)861:2<305:IVAIVM>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
AF-DX 116; ACETYLCHOLINE-RECEPTORS INVIVO; BLOOD-BRAIN-BARRIER; RAT-BRAIN; AUTORADIOGRAPHIC EVIDENCE; ALZHEIMERS-DISEASE; CHOLINERGIC RECEPTORS; POTENTIAL RADIOPHARMACEUTICALS; BINDING-SITES; COMPETITION;
Keywords:
degenerative disease, Alzheimer's - neuropharmacology; acetylcholine receptor, muscarinic; m2 subtype selectivity; regional localization of a receptor; tricyclic compound; tomographic brain imaging;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
49
Recensione:
Indirizzi per estratti:
Indirizzo: Cohen, VI George Washington Univ, Med Ctr, Sect Radiopharmaceut Chem, Walter G Ross Hall,2300 Eye St NW, Washington, DC 20037 USA George Washington Univ Walter G Ross Hall,2300 Eye St NW Washington DC USA 20037
Citazione:
V.I. Cohen et al., "In vitro and in vivo m2 muscarinic subtype selectivity of some dibenzodiazepinones and pyridobenzodiazepinones", BRAIN RES, 861(2), 2000, pp. 305-315

Abstract

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but notmi, subtype receptors in cortical and hippocampal regions of the human brain. Emission tomographic study of the loss of m2 receptors in AD has been limited by the absence of available m2-selective radioligands, which can penetrate the blood-brain barrier. We now report on the in vitro and in vivo m2 muscarinic subtype selectivity of a series of dibenzodiazepinones and pyridobenzodiazepinones determined by competition studies against (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[I-125]IQNB) or [H-3]QNB. Of the compounds examined, three of the 5-[[4-[(4-dialkylamino)butyl]-1-piperidinyl]acetyl]- 10,11-dihydro-5-H-dibenzo[b, e][1,4]diazepin-11-ones (including DIBA) and three of the 11-[[4-[4-(dialkylamino)butyl]-1-phenyl]acetyl]-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-ones (including PBID) exhibited both high binding affinity for the m2 subtype (less than or equal to 5 nM) andhigh m(2)/ml selectivity (greater than or equal to 10). In vive rat brain dissection studies of the competition of PBID or DIED against (R,S)[I-125]IQNB or [H-3]QNB exhibited a dose-dependent preferential decrease in the binding of the radiotracer in brain regions that are enriched in the m2 muscarinic subtype. In vivo rat brain autoradiographic studies of the competitionof PBID, BIBN 99, or DIBD against (R,S)[I-125]IQNB exhibited an insignificant effect of BIBN 99 and confirmed the effect of PBID and DIED in decreasing the binding of (R,S)[I-125]IQNB in brain regions that are enriched in the m2 muscarinic subtype. We conclude that PBID and DIED are potentially useful parent compounds from which in vive m2 selective derivatives may be prepared for potential use in positron emission tomographic (PET) study of theloss of m2 receptors in AD. (C) 2000 Published by Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/11/20 alle ore 18:16:49