Relationships between the chemical structure and pharmacological activities of D(-)S-and L(+)R-tropinoylcholines at cholinergic sites.
D(-)S-and L(+)R-tropinoylcholines were synthesized and their antagonisms to acetylcholine (ACh) were studied at muscarinic receptors (guinea-pig longitudinal ileal muscle), acetylcholinesterase (AChE) and pseudocholinesterase (ChE). Tropinoylcholines were reversible competitive antagonists at muscarinic receptors. D(-)S-tropinoylcholine exhibited a higher affinity as an antagonist at muscarinic receptors than the L(+)R-isomer. ONE MOLECULE OF THE ANTAGONIST COMPETES WITH ONE MOLECULE OF THE AGONIST AT EACH MUSCARINIC RECEPTOR SITE. Tropinoylcholines were competitive inhibitors of AChE. L(+)R-tropinoylcholine exhibited a lower K1 and a higher affinity for AChE. Therefore, muscarinic receptors were stereospecific for the D-configuration, whereas AChE was stereospecific forthe L-configuration of tropinoylcholine. Tropinoylcholines were week agonist at nicotinic receptors (frog rectus abdominis); they were substrates of ChE at low concentrations, but they inhibited ChE partially at high concentrations. L(+)R-tropinoylcholine had a lower apparent Km and a higher affinity than its isomer. Therefore, the esteratic site of ChE is possible stereospecific for the L-configuration of tropinoylcholine. Both tropinoylcholines were mixed inhibitors (competitive and noncompetitive) of ACh hydrolysis by ChE. The results imply that the tropinoylcholines interact at a second site as well as the esteratic site.
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001001:Anura; D001286:Atropine Derivatives / Q000494:pharmacology*; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009184:Mydriatics; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D011817:Rabbits; D011894:Rana pipiens; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001286:Atropine Derivatives; D002800:Cholinesterase Inhibitors; D009184:Mydriatics; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; C014875:tropinoylcholine; D002802:Cholinesterases; D002794:Choline; D000109:Acetylcholine