2-fluoro-3-(4-nitro-phenyl) deschloroepibatidine is a novel potent competitive antagonist of human neuronal α4β2 nAChRs
2-fluoro-3-(4-nitro-phenyl) deschloroepibatidine is a novel potent competitive antagonist of human neuronal α4β2 nAChRs
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DOI：
10.1124/mol.105.021782
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发表时间：
2006-06-01
影响因子：
3.6
通讯作者：
Martin, Billy R.
中科院分区：
文献类型：
--
作者：
Abdrakhmanova, Galya R.;Damaj, M. Imad;Martin, Billy R.
膜片钳技术在一个全细胞配置被用来检查最近开发的2-氟-3-（取代苯基）deschloroepibatidine类似物的功能活性的两个主要亚型的神经元烟碱乙酰胆碱受体（nAChR），α 4 β 2和α 3 β 4，主要在中枢和外周神经系统，分别。这些地棘蛙素类似物先前已显示对α 4 β 2具有高结合亲和力，但对α 7 nAChR不具有高结合亲和力，并在行为疼痛测试中抑制尼古丁诱导的镇痛作用。当对α 4 β 2 nAChR进行电生理学测试时，2-氟-3-（4-硝基-苯基）脱氯地棘蛙素（4-硝基-PFEB）在这些类似物中表现出最显著的拮抗剂活性。它以浓度依赖性方式抑制乙酰胆碱（ACh）诱导的电流，IC 50值为0.1 μ M，并在接近1 μ M的浓度下产生完全抑制。4-Nitro-PFEB在近似1 μ M浓度下，在ACh浓度-反应曲线中产生4倍的位移，而不改变ACh诱导的最大反应。4-硝基-PFEB的这种抑制作用是电压和使用独立的，并且在其类似于1 μ M的浓度下是部分可逆的。在4-nitro-PFEB的存在下，乙酰胆碱诱导的电流的上升和衰减动力学没有改变。与α 4 β 2 nAChR相反，该化合物在接近1 μ M时不影响α 3 β 4 nAChR介导的电流（IC 50接近63.9 μ M）。总的来说，这些功能数据与先前的结合和行为发现一致，并且共同表明，在测试的类似物中，4-硝基-PFEB是α 4 β 2相对于α 3 β 4和α 7 nAChR的最有效和选择性的拮抗剂，通过竞争机制作用于α 4 β 2 nAChR，其效力比二氢-β-赤藓定高17倍。
A patch-clamp technique in a whole-cell configuration was used to examine the functional activity of recently developed 2-fluoro-3-(substituted phenyl)deschloroepibatidine analogs on two major subtypes of neuronal nicotinic acetylcholine receptors (nAChRs), alpha 4 beta 2 and alpha 3 beta 4, that predominate in the central and peripheral nervous systems, respectively. These epibatidine analogs have been shown previously to possess high binding affinity to alpha 4 beta 2 but not to alpha 7 nAChRs and to inhibit nicotine-induced analgesia in behavioral pain tests. The 2-fluoro-3-(4-nitro-phenyl) deschloroepibatidine (4-nitro-PFEB) exhibited the most pronounced antagonist activity among these analogs when tested electrophysiologically on alpha 4 beta 2 nAChRs. It inhibited acetylcholine (ACh)-induced currents in a concentration-dependent manner with an IC50 value of 0.1 mu M and produced complete inhibition at similar to 1 mu M concentration. 4-Nitro-PFEB at similar to 1 mu M concentration produced a 4-fold rightward shift in the ACh concentration-response curve without altering maximum ACh-induced response. This inhibitory effect of 4-nitro-PFEB was voltage- and use-independent and was partially reversible at its similar to 1 mu M concentration. The rise and decay kinetics of ACh-induced currents was not altered in the presence of 4-nitro-PFEB. In contrast to alpha 4 beta 2 nAChRs, this compound did not affect alpha 3 beta 4 nAChR-mediated currents at similar to 1 mu M (IC50 similar to 63.9 mu M). Overall, these functional data agree with previous binding and behavioral findings and suggest collectively that 4-nitro-PFEB is the most effective and selective antagonist of alpha 4 beta 2 versus alpha 3 beta 4 and alpha 7 nAChRs among the tested analogs, acting on alpha 4 beta 2 nAChR through a competitive mechanism with a potency 17-fold higher than that of dihydro-beta-erythroidine.