Portal de Periódicos da CAPES

THE CHOLINERGIC EFFECTS AND RATES OF HYDROLYSIS OF CONFORMATIONALLY RIGID ANALOGS OF ACETYLCHOLINE

1969; American Society for Pharmacology and Experimental Therapeutics; Volume: 166; Issue: 2 Linguagem: Inglês

10.1016/s0022-3565(25)28228-3

1521-0103

C.Y. Chiou, J.P. Long, Joseph G. Cannon, PW Armstrong,

Pharmacogenetics and Drug Metabolism

2-Acetoxy cyclopropyl trimethylammonium iodides (ACTM) are conformationaily rigid analogs of acetylcholine (ACh) with transoid and cisoici conformations. The (+)- trans -ACTM had strong muscarinic activities on clog blood pressure and guinea-pig ileum preparations, suggesting that the transoid form of ACTM was associated with its muscarinic activities. The (+),(-)- cis -ACTM was expected to have strong nicotinic activities owing to its cisoid conformation. However, it had negligible nicotinic activity on frog rectus abdominis muscle, presumably due to the 1,3-interaction of the methylene group of cyclopropane ring with the carbonyl oxygen which is believed to be required for nicotinic activities. The potency ratios of muscarinic activities between (+)-and(-)- trans -ACTM were very close to those between L(+)- and D(-)-acetyl-β-methylcholine. The muscarinic activities of ACh and (+)- trans -ACTM on dog blood pressure were markedly potentiated by neostigmine (41-fold and 23-fold, respectively), but that of (-)- trans -ACTM was poorly potentiated (3-fold). The studies on enzymatic hydrolysis of trans -ACTM by acetylcholinesterase and cholinesterase revealed that the relative rates of hydrolysis of (+)- and (-)- trans -ACTM by acetylcholinesterase were 96 and 59% that of ACh. With the isomers the hydrolysis rates by cholinesterase were 61 and 34% in relation to acetyicholine. These results indicate that the biologic activity of (+)- trans -ACTM is potentiated by neostigmine more than that of (-)- trans -ACTM because the former is a better substitute for the cholinesterases.