Cotinine for Cognitive Impairment in Neurological and Neuropsychiatric Disorders

描述(申请人提供)：近年来，我们的研究结果为可替宁的潜在药理特性提供了新的认识，可替宁是使用烟草产品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，证明可替宁确实是一种具有药理活性的化合物，具有许多表明它可能调节尼古丁的一些有益作用的作用，以及显示其自身的一些独特性质。可替宁被证明在保护培养中的神经样细胞免受细胞毒害方面完全有效(相对于尼古丁)。这种药物在预测抗精神病药物样潜力的大鼠模型中是有效的。可替宁还改善了非人类灵长类动物的工作记忆准确性，这种药物显示出在同一任务的分心版本中增强注意力的能力。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递，但它可以部分脱敏神经节受体，而不影响静息血压。我们建议通过研究可替宁在阿尔茨海默病转基因小鼠模型中的潜在神经保护特性来扩展这些发现。可替宁作为一种典型药物改善精神分裂症认知的潜力，将在持续注意的大鼠模型和工作记忆任务中的猴子身上进行研究，方法是评估该化合物减弱或逆转低剂量拟精神分裂症药物损害效果的能力。最后，可替宁对烟碱受体脱敏的相对能力将通过大鼠和猴子中枢神经系统相关区域的乙酰胆碱释放来确定。我们希望在这些研究完成后，显示可替宁具有可开发的治疗潜力，与以行为和认知障碍以及神经退化为特征的人类疾病有关。基于其增强认知和抗精神病的潜力，可替宁也可能被证明在治疗与精神分裂症相关的认知缺陷方面很有用。也许更重要的是，可替宁有可能作为一种原型制剂，可以用来比较新的药物实体。这项研究的部分翻译设计将提供导致可替宁或相关类似物最终临床试验的结果。

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.