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Titolo:
MUSCARINIC AGONISTS - SYNTHESES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF BICYCLIC ISOXAZOLE ESTER BIOISOSTERES OF NORARECOLINE
Autore:
LENZ SM; MEIER E; PEDERSEN H; FREDERIKSEN K; BOGESO KP; KROGSGAARDLARSEN P;
Indirizzi:
ROYAL DANISH SCH PHARM,DEPT MED CHEM,UNIV PARKEN 2 DK-2100 COPENHAGEN0 DENMARK ROYAL DANISH SCH PHARM,DEPT MED CHEM DK-2100 COPENHAGEN 0 DENMARK H LUNDBECK & CO AS,RES & DEV DK-2500 COPENHAGEN DENMARK
Titolo Testata:
European journal of medicinal chemistry
fascicolo: 4, volume: 30, anno: 1995,
pagine: 263 - 270
SICI:
0223-5234(1995)30:4<263:MA-SAS>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECEPTOR SUBTYPES; ALZHEIMERS-DISEASE; ACETYLCHOLINE; BINDING; NEURONS; PROFILE; BRAIN;
Keywords:
MUSCARINIC ACETYLCHOLINE RECEPTOR; MUSCARINIC AGONIST LIGAND; PARTIAL MUSCARINIC AGONIST; NORARECOLINE BIOISOSTERE; BICYCLIC ISOXAZOLE DERIVATIVE; O-ALKYL-THPO; O-ALKYL-THAO; 7-ME-O-ALKYL-THPO; 8-ME-O-ALLKYL-THAO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
S.M. Lenz et al., "MUSCARINIC AGONISTS - SYNTHESES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF BICYCLIC ISOXAZOLE ESTER BIOISOSTERES OF NORARECOLINE", European journal of medicinal chemistry, 30(4), 1995, pp. 263-270

Abstract

thyl-5,6,7,8-tetrahydra-4H-isoxazolo[4,5-c]azepine (O,8-di-Me-THAO, 2c) and (RS)-8-methyl-3- loxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine (8-Me-O-propargyl-THAO, 2d) have been synthesized and evaluated as muscarinic receptor ligands in receptor binding assays and in in vitro functional assays. The corresponding compounds without methyl groups at C-8, ie O-Me THAO (2a) and O-propargyl-THAO (2b), have previouslybeen shown to exhibit muscarinic agonistic profiles with very little discrimination between M(1)- and M(2)-receptor sites. Based on functional assays, 2c and 2d were found to be less efficacious than 2a and 2b, respectively, and 2d proved to be an M(1)-selective partial agonist. The-affinity and M(1) efficacy of 2c and 2d were comparable to those of the corresponding six-membered ring analogues, methyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine (O,7-di-Me-THPO, 1c) and rgyloxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine (7-Me-O-propargyl-THPO, 1d). However, neither compound 1c nor compound 1d-displayed M(1) selectivity. In summary, within this class of bicyclic muscaninic agonists, replacement of 3-methoxy by 3-propargyloxy groups generally increases muscarinic affinity without effecting the efficacy at M(1) receptors significantly. Introduction of a methyl group into the saturated ring, at the position alpha to the C-5 of the isoxazole ring (alpha-position) lead to compounds exerting lower efficacy and, in the case of compound 2d, an increased selectivity with respect to M(1) agonism.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 16/07/20 alle ore 19:59:37