Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor
Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor
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DOI：
10.1124/jpet.110.173245
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发表时间：
2011-02-01
影响因子：
3.5
通讯作者：
Lesage, Anne S. J.
中科院分区：
文献类型：
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作者：
Dinklo, Theo;Shaban, Hamdy;Lesage, Anne S. J.
α（7）烟碱乙酰胆碱受体（nAChR）是治疗与精神分裂症、阿尔茨海默病、帕金森病和注意力缺陷/多动障碍相关的认知缺陷的潜在治疗靶点。在动物模型和早期临床试验中，α（7）nAChRs的激活改善了感觉门控和认知功能。在此，我们描述了新型高选择性α（7）nAChR正变构调节剂2-[[4-氟-3-（三氟甲基）苯基]氨基]-4-（4-吡啶基）-5-噻唑甲醇（JNJ-1930942）。该化合物增强表达克隆的人α（7）nAChR的GH4 C1细胞系中胆碱诱发的细胞内Ca 2+水平升高。JNJ-1930942不作用于α 4 β 2、α 3 β 4 nAChR或相关5-HT 3A通道。在GH4 C1细胞系中进行的电生理学评估显示，JNJ-1930942增加了对胆碱、乙酰胆碱和N-[（3R）-1-氮杂双环[2.2.2]辛-3-基]-4-氯苯甲酰胺（PNU-282987）的峰值和净电荷响应。增强作用主要通过影响受体脱敏特性来获得，使激活和失活动力学以及从脱敏中恢复相对不变。胆碱功效在其全浓度响应范围内增加，并且胆碱效力增加超过10倍。增强作用是α（7）通道依赖性的，因为它被α（7）拮抗剂甲基甘草次酸阻断。此外，在海马切片中，JNJ-1930942可增强海马齿状回突触的神经传递，并促进齿状回电诱发突触反应的长时程增强。在体内，JNJ-1930942逆转DBA/2小鼠中基于遗传的听觉门控缺陷。JNJ-1930942将是研究α（7）nAChR增强作用在中枢神经系统疾病（假设涉及α（7）nAChR神经传递缺陷）中的治疗潜力的有用工具。
The alpha(7) nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimer's disease, Parkinson's disease, and attention-deficit/hyperactivity disorder. Activation of alpha(7) nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective alpha(7) nAChR positive allosteric modulator, 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942). This compound enhances the choline-evoked rise in intracellular Ca2+ levels in the GH4C1 cell line expressing the cloned human alpha(7) nAChR. JNJ-1930942 does not act on alpha 4 beta 2, alpha 3 beta 4 nAChRs or on the related 5-HT3A channel. Electrophysiological assessment in the GH4C1 cell line shows that JNJ-1930942 increases the peak and net charge response to choline, acetylcholine, and N-[(3R)-1-azabicyclo[2.2.2] oct-3-yl]-4-chlorobenzamide (PNU-282987). The potentiation is obtained mainly by affecting the receptor desensitization characteristics, leaving activation and deactivation kinetics as well as recovery from desensitization relatively unchanged. Choline efficacy is increased over its full concentration response range, and choline potency is increased more than 10-fold. The potentiating effect is alpha(7) channel-dependent, because it is blocked by the alpha(7) antagonist methyllycaconitine. Moreover, in hippocampal slices, JNJ-1930942 enhances neurotransmission at hippocampal dentate gyrus synapses and facilitates the induction of long-term potentiation of electrically evoked synaptic responses in the dentate gyrus. In vivo, JNJ-1930942 reverses a genetically based auditory gating deficit in DBA/2 mice. JNJ-1930942 will be a useful tool to study the therapeutic potential of alpha(7) nAChR potentiation in central nervous system disorders in which a deficit in alpha(7) nAChR neurotransmission is hypothesized to be involved.