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

¹ Department of Pharmacology, College of Medicine and Division of Medicinal Chemistry. College of Pharmacy, University of Iowa, Iowa City, Iowa
² Department of Pharmacology, College of Medicine and Division of Medicinal Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa

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--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.