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.
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.
Jeppesen
L
L
Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, DK-2760 Mâlov, Denmark.
Olesen
P H
PH
Hansen
L
L
Sheardown
M J
MJ
Thomsen
C
C
Rasmussen
T
T
Jensen
A F
AF
Christensen
M S
MS
Rimvall
K
K
Ward
J S
JS
Whitesitt
C
C
Calligaro
D O
DO
Bymaster
F P
FP
Delapp
N W
NW
Felder
C C
CC
Shannon
H E
HE
Sauerberg
P
P
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
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