Buccafusco J J, Aronstam R S
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912-3368.
Neuropharmacology. 1988 Mar;27(3):227-33. doi: 10.1016/0028-3908(88)90038-x.
The purpose of this study was to determine whether a series of analogs of choline depress central cholinergic function in a manner consistent with the activity of their acetylated derivatives. Intracerebroventricular infusion of monoethylcholine (MECh), diethylcholine (DECh) and triethylcholine (TECh) inhibited the pressor response of unanesthetized rats to the subsequent intravenous injection of physostigmine (a well-characterized muscarinic response). The order of blocking potency was TECh greater than DECh greater than MECh greater than choline, directly opposite to the order of potency for elicitation of a central pressor response by their associated acetylated derivative (i.e. ACh greater than AMECh greater than ADECh = ATECh; Aronstam, Marshall and Buccafusco, 1988). In contrast, there was little selectivity between the analogs of choline in terms of their affinity for muscarinic receptors in the brainstem or cortex; the Ki's for inhibition of the binding of [3H]quinuclidinyl benzilate ranged from 0.33 to 0.95 mM). In terms of their affinity for nicotinic receptors (from the electric organ of Torpedo californica) the following order of potency was obtained: choline greater than MECh = DECh greater than TECh. Choline and MEC stimulated the binding of [3H]phencyclidine to the nicotinic ion channel (EC50's = 79 and 115 microM, respectively). At greater concentrations, all of the analogs inhibited ligand binding to the channel (Ki's from 0.2 to 10 mM), with the following order of potency: TECh greater than DECh greater than MECh greater than choline. These findings suggest that the inhibitory actions of these analogs of choline are related to their synthesis and release as false cholinergic neurotransmitters.
本研究的目的是确定一系列胆碱类似物是否以与其乙酰化衍生物活性一致的方式抑制中枢胆碱能功能。向未麻醉大鼠脑室内注入单乙胆碱（MECh）、二乙胆碱（DECh）和三乙胆碱（TECh）可抑制其对随后静脉注射毒扁豆碱（一种特征明确的毒蕈碱反应）的升压反应。阻断效力顺序为TECh＞DECh＞MECh＞胆碱，这与它们相关的乙酰化衍生物引发中枢升压反应的效力顺序（即ACh＞AMECh＞ADECh = ATECh；Aronstam、Marshall和Buccafusco，1988）直接相反。相比之下，胆碱类似物对脑干或皮质毒蕈碱受体的亲和力几乎没有选择性；抑制[3H]喹核醇基苯甲酸酯结合的Ki值范围为0.33至0.95 mM）。就它们对烟碱受体的亲和力（来自加州电鳐的电器官）而言，获得了以下效力顺序：胆碱＞MECh = DECh＞TECh。胆碱和MEC刺激了[3H]苯环利定与烟碱离子通道的结合（EC50分别为79和115 microM）。在更高浓度下，所有类似物均抑制配体与通道的结合（Ki值为0.2至10 mM），效力顺序如下：TECh＞DECh＞MECh＞胆碱。这些发现表明，这些胆碱类似物的抑制作用与其作为假胆碱能神经递质的合成和释放有关。
