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.
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.
authors.affiliation: Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, DK-2760 Mâlov, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Jeppesen
authors.forename: P H
authors.initials: PH
authors.lastname: Olesen
authors.forename: L
authors.initials: L
authors.lastname: Hansen
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
authors.forename: T
authors.initials: T
authors.lastname: Rasmussen
authors.forename: A F
authors.initials: AF
authors.lastname: Jensen
authors.forename: M S
authors.initials: MS
authors.lastname: Christensen
authors.forename: K
authors.initials: K
authors.lastname: Rimvall
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: C
authors.initials: C
authors.lastname: Whitesitt
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: N W
authors.initials: NW
authors.lastname: Delapp
authors.forename: C C
authors.initials: CC
authors.lastname: Felder
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D016466:CHO Cells; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D006536:Heptanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D051379:Mice; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection
chemical_list: D001372:Aza Compounds; D006536:Heptanes; D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D000242:Cyclic AMP