| Title : 1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives - Jeppesen_1999_J.Med.Chem_42_1999 |
| Author(s) : Jeppesen L , Olesen PH , Hansen L , Sheardown MJ , Thomsen C , Rasmussen T , Jensen AF , Christensen MS , Rimvall K , Ward JS , Whitesitt CA , Calligaro DO , Bymaster FP , DeLapp NW , Felder CC , Shannon HE , Sauerberg P |
| Ref : Journal of Medicinal Chemistry , 42 :1999 , 1999 |
|
Abstract :
Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 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. |
| PubMedSearch : Jeppesen_1999_J.Med.Chem_42_1999 |
| PubMedID: 10354408 |
Jeppesen L, Olesen PH, Hansen L, Sheardown MJ, Thomsen C, Rasmussen T, Jensen AF, Christensen MS, Rimvall K, Ward JS, Whitesitt CA, Calligaro DO, Bymaster FP, DeLapp NW, Felder CC, Shannon HE, Sauerberg P (1999)
1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives
Journal of Medicinal Chemistry
42 :1999
Jeppesen L, Olesen PH, Hansen L, Sheardown MJ, Thomsen C, Rasmussen T, Jensen AF, Christensen MS, Rimvall K, Ward JS, Whitesitt CA, Calligaro DO, Bymaster FP, DeLapp NW, Felder CC, Shannon HE, Sauerberg P (1999)
Journal of Medicinal Chemistry
42 :1999