Muscarinic cholinergic agonists and antagonists of the 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridine type. Synthesis and structure-activity relationships.
A series of 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyr idines (2a-q) were synthesized and tested for central muscarinic cholinergic receptor binding affinity by using [3H]oxotremorine-M and [3H]QNB as ligands and in a functional assay using guinea pig ileum. The analogues with unbranched C1-8-alkyl substituents (2a-g) were agonists, whereas the compounds with branched or cyclic substituents (2h-m) were antagonists. The alkyl ether analogues (2o-q) were also agonists but had lower receptor binding affinity than the corresponding alkyl analogues. The 3-(5-alkyl-1,2,4-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridi ne analogues had only ver low affinity for the central muscarinic receptors and were weak antagonists in the ileum assay. A few 3-(3-butyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyr idines substituted with methyl or hydrogen in the 1-, 5-, or 6-position were synthesized and tested. N-Desmethyl analogue 7 was a potent muscarinic agonist, whereas N-desmethyl-5-methyl analogue 11 and N-methyl-6-methyl analogue 13 both were antagonists with lower muscarinic receptor affinity. The 3-(3-butyl-1,2,4-oxadiazol-5-yl)quinuclidine (17) and tropane (15) analogues were both very potent antagonists with high affinity for central muscarinic receptors. The ratio [IC50(QNB)/IC50(Oxo-M)] x 0.162 proved to be a good indicator of the efficacy of the compounds in the guinea pig ileum assay.
Sauerberg
P
P
Ferrosan A/S, CNS Division, Soeborg, Denmark.
Kindtler
J W
JW
Nielsen
L
L
Sheardown
M J
MJ
Honoré
T
T
D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects; D013329:Structure-Activity Relationship
D001391:Azo Compounds; D010276:Parasympatholytics; D010277:Parasympathomimetics; D011725:Pyridines; D011976:Receptors, Muscarinic