Relationships between the chemical structure and pharmacological activities of D (-) S-and L (+) R-tropinoylcholines at cholinergic sites
Sastry, B.V.; Cheng, H.C.
Journal of Pharmacology and Experimental Therapeutics 202(1): 105-115
1977
ISSN/ISBN: 0022-3565 PMID: 301565 Document Number: 121122
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.