In Silico Biosciences, Berwyn, USA.
Expert Opin Investig Drugs. 2012 Jan;21(1):59-65. doi: 10.1517/13543784.2012.633510. Epub 2011 Nov 3.
Nicotinic receptors (nAChR), a class of ligand-gated ion channels, are attractive targets in a variety of CNS diseases. The low-affinity α7 nAChR modulate the levels of various neurotransmitters, their receptor density is affected in schizophrenia and a single nucleotide polymorphism in the promoter region has been associated with higher risk for schizophrenia.
This article reviews the scientific rationale for α7 nAChR stimulation and presents a selection of α7-positive modulators that are in development for cognitive deficits, both in Alzheimer's disease and in cognitive impairment associated with schizophrenia. The available clinical information is reviewed and the translational difficulties are discussed.
In contrast to preclinical models, clinical proof-of-concept studies so far have not shown clear unequivocal cognitive benefit, although there are signs of clinical efficacy on specific cognitive scales and on negative symptoms. Possible problems associated with the clinical development include the impact of dosage and dosing schedule on the balance between activation and desensitization of the ion channel, the selection of comedication, robust human target engagement data and the choice of clinical readout scales. A better understanding of the human biology of α7 nAChR is essential for improving the successful clinical development of this promising target.
烟碱型乙酰胆碱受体（nAChR）是一类配体门控离子通道，在各种中枢神经系统疾病中是有吸引力的靶点。低亲和力的α7 nAChR 调节各种神经递质的水平，其受体密度在精神分裂症中受到影响，启动子区域的单核苷酸多态性与精神分裂症的更高风险相关。
本文综述了 α7 nAChR 刺激的科学原理，并介绍了一些正在开发中的用于治疗阿尔茨海默病和与精神分裂症相关的认知障碍的 α7 阳性调节剂。综述了现有临床信息，并讨论了转化中的困难。
与临床前模型相比，迄今为止的临床概念验证研究并未显示出明确的认知益处，尽管在特定的认知量表和阴性症状上有临床疗效的迹象。与临床开发相关的可能问题包括剂量和给药方案对离子通道激活和脱敏之间平衡的影响、伴随药物的选择、强有力的人类靶标结合数据以及临床检测量表的选择。更好地了解 α7 nAChR 的人类生物学对于改善这一有前途的靶点的成功临床开发至关重要。
