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Titolo:
CONFORMATIONALLY CONSTRAINED ANALOGS OF THE MUSCARINIC AGONIST IADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE - SYNTHESIS, RECEPTOR AFFINITY, AND ANTINOCICEPTIVE ACTIVITY
Autore:
SAUERBERG P; OLESEN PH; SHEARDOWN MJ; RIMVALL K; THOGERSEN H; SHANNON HE; SAWYER BD; WARD JS; BYMASTER FP; DELAPP NW; CALLIGARO DO; SWEDBERG MDB;
Indirizzi:
NOVO NORDISK AS,HLTH CARE DISCOVERY,NOVO NORDISK PK DK-2760 MALOV DENMARK ELI LILLY & CO,LILLY RES LABS,NEUROSCI RES INDIANAPOLIS IN 46285
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 1, volume: 41, anno: 1998,
pagine: 109 - 116
SICI:
0022-2623(1998)41:1<109:CCAOTM>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
MORPHINE; DRUGS; MOUSE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
26
Recensione:
Indirizzi per estratti:
Citazione:
P. Sauerberg et al., "CONFORMATIONALLY CONSTRAINED ANALOGS OF THE MUSCARINIC AGONIST IADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE - SYNTHESIS, RECEPTOR AFFINITY, AND ANTINOCICEPTIVE ACTIVITY", Journal of medicinal chemistry, 41(1), 1998, pp. 109-116

Abstract

Conformationally constrained analogues of the potent muscarinic agonist iadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (methylthio-TZTP, 17) were designed and synthesized with the aim of (a) improving the antinociceptive selectivity over salivation and tremor and (b) predicting the active conformation of 17 with respect to the dihedral angle C4-C3-C3'-N2'. Using MOPAC 6.0 tricyclic analogues (7, 15, 16) with C4-C3-C3'-N2' dihedral angles close to 180 degrees and a rotation hindered analogue (9) with a C4-C3-C3'-N2' dihedral angle close to 274 degrees were designed, as these conformations had previously been suggested as being the active conformations. The analogues were tested for central muscarinic receptor binding affinity, for their antinociceptive activity in the mouse grid shock test, and, in the same assay, for their ability to induce tremor and salivation. The data showed that the tricyclic analogues (7, 15, 16) were equipotent with 17 as analgesics, butwith no improved side effect profiles. The rotation-hindered analogue9 had neither muscarinic receptor binding affinity nor antinociceptive activity. These results suggest that the active conformation of 17 has a C3-C4-C3'-N2' dihedral angle close to 180 degrees.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 08:42:35