Sastry B V, Jaiswal N, Janson V, Day P S, Naukam R J
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Pharmacol Res Commun. 1988 Sep;20(9):751-71. doi: 10.1016/s0031-6989(88)80715-x.
A choline acetyltransferase (ChA) inhibitor with an optimum combination of properties of potency, stability and membrane permeability is required to study several functional aspects of acetylcholine in nervous and non-nervous tissues. Therefore, 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA), 2-(beta-naphthoyl)ethyltrimethylammonium iodide (beta-NETA), 2-(9'-anthroyl)ethyltrimethylammonium iodide (9'-AETA) and their corresponding tertiary dimethylamine hydrochloride analogs (alpha-NEDA, beta-NEDA, 9'-AEDA) were synthesized and tested for their ChA inhibitory activities. The quaternary ammonium compounds were more potent inhibitors (150 in microM: alpha-NETA, 9; beta-NETA, 76; 9'-AETA, 32) than the corresponding tertiary compounds (150 in microM: alpha-NEDA, 63; beta-NEDA, 1400; 9'-AEDA, 77). The alpha-naphthyl moiety was preferable to the beta-naphthyl- or 9'-anthryl moieties for alignment with the enzyme for inhibition. alpha-NETA and alpha-NEDA exhibited adequate ChA inhibitory potencies for further pharmacological studies and localization of membrane bound ChA. They exhibited fluorescent characteristics of the alpha-naphthyl moiety. Their ChA inhibition was not reversible by dialysis. They were considerably more potent for inhibiting ChA than cholinesterases and carnitine acetyltransferase.
为了研究神经组织和非神经组织中乙酰胆碱的几个功能方面，需要一种具有效力、稳定性和膜通透性最佳组合的胆碱乙酰转移酶（ChA）抑制剂。因此，合成了2-(α-萘甲酰基)乙基三甲基碘化铵（α-NETA）、2-(β-萘甲酰基)乙基三甲基碘化铵（β-NETA）、2-(9'-蒽甲酰基)乙基三甲基碘化铵（9'-AETA）及其相应的叔二甲基胺盐酸盐类似物（α-NEDA、β-NEDA、9'-AEDA），并测试了它们对ChA的抑制活性。季铵化合物比相应的叔化合物（150 μM时：α-NEDA为63；β-NEDA为1400；9'-AEDA为77）是更有效的抑制剂（150 μM时：α-NETA为150；β-NETA为9；9'-AETA为32）。α-萘基部分比β-萘基或9'-蒽基部分更有利于与酶结合以进行抑制。α-NETA和α-NEDA表现出足够的ChA抑制效力，可用于进一步的药理学研究和膜结合ChA的定位。它们表现出α-萘基部分的荧光特性。它们对ChA的抑制作用不能通过透析逆转。它们抑制ChA的效力比胆碱酯酶和肉碱乙酰转移酶强得多。
