Muscarinic agonists with antipsychotic-like activity: structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity.
Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type muscarinic partial agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that muscarinic agonists act as functional dopamine antagonists and that they could become a novel treatment of psychotic patients.
Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, 2760 Mâlov, Denmark, and Neuroscience Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA. psa@novo.dk
P
P
Sauerberg
L
L
Jeppesen
P H
PH
Olesen
T
T
Rasmussen
M D
MD
Swedberg
M J
MJ
Sheardown
A
A
Fink-Jensen
C
C
Thomsen
H
H
Thøgersen
K
K
Rimvall
J S
JS
Ward
D O
DO
Calligaro
N W
NW
DeLapp
F P
FP
Bymaster
H E
HE
Shannon
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012472:Salivation / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014202:Tremor / Q000139:chemically induced
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D018721:Muscarinic Agonists; D013830:Thiadiazoles