2. Academic Validation
  3. 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

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

  • J Med Chem. 1999 Jun 3;42(11):1999-2006. doi: 10.1021/jm9910019.
L Jeppesen 1,  P H Olesen,  L Hansen,  M J Sheardown,  C Thomsen,  T Rasmussen,  A F Jensen,  M S Christensen,  K Rimvall,  J S Ward,  C Whitesitt,  D O Calligaro,  F P Bymaster,  N W Delapp,  C C Felder,  H E Shannon,  P Sauerberg
Affiliations

Affiliation

  • 1 Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, DK-2760 Mâlov, Denmark.
PMID: 10354408 DOI: 10.1021/jm9910019
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.

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