Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogues of trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol).
Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogues of trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol).
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反式-2-(4-苯基哌啶基)环己醇（vesamicol）的衍生物和类似物的合成、体外乙酰胆碱储存阻断活性以及生物学特性。
DOI：
10.1021/jm00126a013
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发表时间：
1989
影响因子：
7.3
通讯作者：
Kirtman,B
中科院分区：
文献类型：
--
作者：
Rogers,GA;Parsons,SM;Anderson,DC;Nilsson,LM;Bahr,BA;Kornreich,WD;Kaufman,R;Jacobs,RS;Kirtman,B
合成了乙酰胆碱储存阻断药物反式-2-(4-苯基哌啶基)-环己醇（维沙考）的 84 种类似物和衍生物，并利用来自鱼雷电器官的纯化突触小泡通过乙酰胆碱主动转运测定法评估了它们的效力。母体药物具有对映选择性，(-)-vesamicol 的效力比 (+)-vesamicol 强 25 倍。 (+)-vesamicol的原子结构和绝对构型通过X射线晶体学测定。 (-)-维沙考的绝对构型为1R、2R。结构-活性证据表明 (-)-vesamicol 不充当乙酰胆碱类似物。对所有三个环的改变会对效力产生很大影响。出乎意料的是，跨双赤道或跨二轴锁定醇和铵基团的类似物均表现出良好的效力。已发现一种有效的苯并维沙米考家族，适合于轻松加工亲和标记和亲和层析应用中有用的种类。通过乙酰胆碱转运测定评估的效力与小鼠的LD^值之间发现了良好的相关性。许多小组正在研究神经末梢突触小泡储存乙酰胆碱(ACh)的生化和生理机制。 1 除了质子泵浦 ATP 酶和乙酰胆碱转运蛋白外，还存在化合物反式-2-(4-苯基哌啶基)环己醇的受体。 2 当受体被药物占据时，会发生乙酰胆碱储存的非竞争性抑制。 3 该药物（以前称为 AH5183，但现在称为 vesam-icol1’4）对于研究完整神经末梢制剂中的 ACh 代谢具有特殊价值（参考文献 1 中综述）。虽然使用高度纯化的鱼雷电器官突触小泡进行生化研究是完全令人满意的，但维萨米考在完整的制剂中表现出一些非特异性。例如，在由于乙酰胆碱储存阻滞而导致神经肌肉阻滞之前，肌肉收缩响应间接的幅度
Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)-cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ. Theparent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol. The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography. The absolute configuration of (-)-vesamicol is 1R, 2R. Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue. Alterations to all three rings can have large effects on potency. Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency. A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications. A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD^ values in mouse.The biochemical and physiological mechanisms of ace-tylcholine (ACh) storage by nerve terminal synaptic ves-icles are being studied by many groups. 1 In addition to a proton-pumping ATPase and ACh transporter, a receptor for the compound trans-2-(4-phenylpiperidino) cyclohexanol is present. 2 When the receptor is occupied by drug, noncompetitive inhibition of ACh storage occurs. 3 The drug (formerly called AH5183 but now called vesam-icol1’4) has been of particular value to the study of ACh metabolism in intact nerve terminal preparations (reviewed in ref 1). While it is entirely satisfactory for biochemical studies utilizing highly purified Torpedo electric organ synaptic vesicles, vesamicol exhibits some nonspecificity in intact preparations. For example, before neuromuscular block sets in as a result of the ACh storage block, the amplitude of muscle contraction in response to indirect