Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic m1 receptor activation.
Series of analogs to the functional m1 selective agonist, xanomeline (hexyloxy-TZTP), were evaluated for their in vitro m1 efficacy in cell lines transfected with the human m1 receptor. Systematic variation of the side chain and the azacyclic ring led to the discovery of potent muscarinic agonists with robust m1 efficacy, all having the phenylpropargyloxy/thio as the side chain. The most selective compound was the phenylpropargylthio-[3.2.1] endo analog 28, which is a potent and efficacious m1 agonist with no m2 activity.
Sauerberg
P
P
Novo Nordisk A/S, Health Care Discovery, Måløv, Denmark. psa@novo.dk
Jeppesen
L
L
Olesen
P H
PH
Sheardown
M J
MJ
Fink-Jensen
A
A
Rasmussen
T
T
Rimvall
K
K
Shannon
H E
HE
Bymaster
F P
FP
DeLapp
N W
NW
Calligaro
D O
DO
Ward
J S
JS
Whitesitt
C A
CA
Thomsen
C
C
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D020128:Inhibitory Concentration 50; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology; D014162:Transfection
D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; C075257:xanomeline