A novel series of non-quaternary oxadiazoles acting as full agonists at muscarinic receptors.
1 A novel series of non-quaternary oxadiazole-based muscarinic agonists demonstrated high affinity for muscarinic receptors. 2. These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations. 3. Two amino oxadiazoles, one from a quinuclidine series (L-660,863) and one from a 1-azanorbornane series (L-670,207) possessed a high ratio of potency for displacing the binding of [3H]-N-methyl-scopolamine ([3H]-NMS) to potency for displacing the agonist [3H]-oxotremorine-M cortex. 4. The two azanorbornane derivatives L-670,548 and L-670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED50 0.26 and 0.18 microM respectively). 5. The maximum response obtained with L-670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine. 6. These oxadiazole muscarinic agonists are among the most potent and efficacious non-quaternary muscarinic agonists ever described.
Freedman
S B
SB
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
Harley
E A
EA
Patel
S
S
Newberry
N R
NR
Gilbert
M J
MJ
McKnight
A T
AT
Tang
J K
JK
Maguire
J J
JJ
Mudunkotuwa
N T
NT
Baker
R
R
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010277:Parasympathomimetics; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D010069:Oxadiazoles; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic