1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M-1 agonists: Structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives

Authors
Jeppesen, L Olesen, PH Hansen, L Sheardown, MJ Thomsen, C Rasmussen, T Jensen, AF Christensen, MS Rimvall, K Ward, JS Whitesitt, C Calligaro, DO Bymaster, FP Delapp, NW Felder, CC Shannon, HE Sauerberg, P
Citation
L. Jeppesen et al., 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M-1 agonists: Structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives, J MED CHEM, 42(11), 1999, pp. 1999-2006
Citations number
20
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
42
Issue
11
Year of publication
1999
Pages
1999 - 2006
Database
ISI
SICI code
0022-2623(19990603)42:11<1999:1ANP>2.0.ZU;2-7
Abstract
Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]hept anes were synthesized and evaluated for their in vitro activity in cell lin es transfected with either the human M-1 or M-2 receptor. 3-Phenyl-2-propyn -1-yloxy and -1-ylthio analogues substituted with halogen in the meta posit ion showed high functional potency, efficacy, and selectivity toward the M- 1 receptor subtype. A quite unique functional M-1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.