Cotinine for Cognitive Impairment in Neurological and Neuropsychiatric Disorders

描述（由申请人提供）：近年来，我们的研究成果为可替宁的潜在药理学特性提供了新的认识，可替宁是烟草制品使用后产生的尼古丁的主要代谢物。我们现在提供了令人信服的证据，表明可替宁确实是一种具有药理活性的化合物，具有许多作用，表明它可能介导尼古丁的一些有益作用，同时也显示出它自己的一些独特特性。可替宁被证明在保护培养的神经样细胞免受细胞毒性损伤方面具有完全的功效（相对于尼古丁）。这种药物在预测抗精神病药物潜力的大鼠模型中是有效的。可替宁还提高了非人类灵长类动物的工作记忆准确性，并且在同一任务的分心版本中表现出了提高注意力的能力。最后，我们证明，与尼古丁不同，可替宁不能刺激清醒大鼠的自主神经节传导，但它能部分脱敏神经节受体，而不影响静息血压。我们建议通过在阿尔茨海默病转基因小鼠模型中研究可替宁潜在的神经保护特性来扩展这些发现。可替宁作为一种改善精神分裂症患者认知的典型药物的潜力，将在持续注意力的大鼠模型和工作记忆任务中的猴子身上进行研究，通过评估该化合物减弱或逆转低剂量拟精神药物的损害作用的能力。最后，通过测定大鼠和猴中枢神经系统相关区域乙酰胆碱释放量，确定可替宁对烟碱受体脱敏的相对能力。我们期望在完成这些研究时表明，可替宁对以行为和认知障碍以及神经变性为特征的人类疾病具有可开发的治疗潜力。基于其认知增强和抗精神病的潜力，可替宁也可能被证明对难以治疗的与精神分裂症相关的认知缺陷有用。也许更重要的是，可替宁有潜力作为一种原型剂，可以与新的药物实体进行比较。该研究的部分翻译设计将提供结果，最终导致可替宁或相关类似物的临床试验。

DESCRIPTION (provided by applicant): In recent years our research findings have provided a new appreciation for the potential pharmacological properties of cotinine, the principal metabolite of nicotine produced after using tobacco products. We now provide compelling evidence that cotinine is indeed a pharmacologically active compound having a number of actions that suggest that it might mediate some of the beneficial effects of nicotine, as well as exhibiting some unique properties of its own. Cotinine was shown to have full efficacy (relative to nicotine) in protecting neural-like cells in culture from a cytotoxic insult. The drug was active in a rat model that predicts antipsychotic-like potential. Cotinine also improved working memory accuracy by non-human primates, and the drug exhibited ability to enhance attention in a distractor version of the same task. Finally we demonstrated that unlike nicotine, cotinine failed to stimulate autonomic ganglionic transmission in the awake rat, but it partly desensitized ganglionic receptors without affecting resting blood pressure. We propose to extend these findings by studying the potential neuroprotective properties of cotinine in a transgenic mouse model of Alzheimer's disease. The potential of cotinine as a prototypical agent to improve cognition in schizophrenia will be studied in a rat model of sustained attention and in monkeys in a working memory task by evaluating the ability of the compound to attenuate or reverse the impairing effects of low doses of psychotomimetic agents. Finally, the relative ability of cotinine to desensitize nicotinic receptors will be determined in of acetylcholine release from relevant regions of rat and monkey CNS. We expect at the completion of these studies to show that cotinine has exploitable therapeutic potential relevant to human diseases that feature behavioral and cognitive impairment and neurodegeneration. Based on its cognition-enhancing and antipsychotic potential, cotinine also could prove useful in the difficult to treat cognitive deficits associated with schizophrenia. Perhaps even more importantly cotinine has the potential to serve as a prototypical agent by which new drug entities may be compared. The partly translational design of the study will provide results leading to eventual clinical trials with cotinine or a relevant analog.