Muscarinic agonists as analgesics. Antinociceptive activity versus M1 activity: SAR of alkylthio-TZTP's and related 1,2,5-thiadiazole analogs.
Alkylthio-TZTPs (3-(3-alkylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-met hylpyridines) and corresponding azabicyclic analogs were tested for m1 efficacy in cloned human m1 receptors and for antinociceptive activity in the mouse grid shock assay. The m1 (%PI) SAR were distinctly different from the analgesia and the salivation SAR, suggesting that analgesia is mediated by neither m1 nor M3 muscarinic receptors.
Sauerberg
P
P
Novo Nordisk A/S, Pharmaceuticals Division, Drug Discovery, Måløv, Denmark.
Olesen
P H
PH
Sheardown
M J
MJ
Suzdak
P D
PD
Shannon
H E
HE
Bymaster
F P
FP
Calligaro
D O
DO
Mitch
C H
CH
Ward
J S
JS
Swedberg
M D
MD
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010277:Parasympathomimetics / Q000737:chemistry / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014828:Vocalization, Animal / Q000187:drug effects
D000700:Analgesics; D018721:Muscarinic Agonists; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; C075258:3-(3-(hexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; D002217:Carbachol