Pfizer Global Research & Development, Pfizer Inc., Eastern Point Rd, Groton, Connecticut 06340, USA.
Curr Pharm Des. 2010;16(5):538-54. doi: 10.2174/138161210790361434.
The most abundant homomeric nicotinic acetylcholine receptors (nAChRs) in the mammalian brain are the pentameric alpha7 nAChRs which consist of five alpha7 subunits, and each subunit provides an orthosteric low affinity binding site for its endogenous ligand, acetylcholine. Distribution and high level expression of alpha7 nAChRs within the limbic circuitry, including the hippocampus and prefrontal cortical areas are in line with their involvement in various cognitive functions. Activation of alpha7 nAChRs generates a conformational change of sub-unit proteins, making the channel permeable to cations, in particular calcium, leading to change in neuronal activity and excitability, and via increased intracellular calcium, modulating transmitter release and neuronal network activity. Since genetic linkage studies implicated the alpha7 nAChRs subunit gene CHRNA7 in schizophrenia, there is a considerable interest for developing drug therapies targeting alpha7 nAChRs. In this review recent development of selective agonists and positive allosteric modulators of alpha7 nAChRs are discussed. In addition to summarizing medicinal chemistry efforts, both cellular and neuronal network pharmacology of alpha7 nAChRs are covered. The association between CHRNA7 gene and impaired P50 auditory gating has provided an attractive endophenotype, and its use as a potential translational biomarker for alpha7 nAChRs drug discovery is discussed. Preliminary clinical findings on alpha7 nAChRs agonists are also summarized.
在哺乳动物大脑中，最丰富的同型烟碱型乙酰胆碱受体（nAChRs）是五聚体α7 nAChRs，由五个α7 亚基组成，每个亚基为其内源性配体乙酰胆碱提供一个正位低亲和力结合位点。α7 nAChRs 在边缘回路中的分布和高水平表达，包括海马体和前额叶皮层区域，与其在各种认知功能中的参与一致。α7 nAChRs 的激活会导致亚基蛋白构象发生变化，使通道对阳离子（特别是钙离子）通透，从而导致神经元活动和兴奋性发生变化，并通过增加细胞内钙离子来调节递质释放和神经元网络活动。由于遗传连锁研究将α7 nAChRs 亚基基因 CHRNA7 与精神分裂症联系在一起，因此开发针对α7 nAChRs 的药物治疗方法引起了相当大的兴趣。在这篇综述中，讨论了α7 nAChRs 的选择性激动剂和正变构调节剂的最新进展。除了总结药物化学方面的努力外，还涵盖了α7 nAChRs 的细胞和神经元网络药理学。CHRNA7 基因与 P50 听觉门控受损之间的关联提供了一个有吸引力的内表型，并且讨论了将其用作 α7 nAChRs 药物发现的潜在转化生物标志物的可能性。还总结了α7 nAChRs 激动剂的初步临床发现。
