Cotinine for Cognitive Impairment in Neurological and Neuropsychiatric Disorders

描述（由申请人提供）：近年来，我们的研究结果为可替宁（使用烟草产品后产生的尼古丁的主要代谢产物）的潜在药理学特性提供了新的认识。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多种作用的尼古丁活性化合物，表明它可能介导尼古丁的一些有益作用，并表现出其自身的一些独特特性。可替宁显示出在保护培养物中的神经样细胞免受细胞毒性损伤方面具有完全功效（相对于尼古丁）。该药物在预测抗精神病样潜力的大鼠模型中具有活性。可替宁还可以提高非人类灵长类动物工作记忆的准确性，并且该药物在同一任务的干扰物版本中表现出增强注意力的能力。最后，我们证明，与尼古丁不同，可替宁未能刺激清醒大鼠的自主神经节传递，但它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。将在大鼠持续注意力模型和猴工作记忆任务中，通过评价化合物减弱或逆转低剂量拟精神病药物损害作用的能力，研究可替宁作为原型药物改善精神分裂症认知的潜力。最后，可替宁使烟碱受体脱敏的相对能力将在大鼠和猴CNS相关区域的乙酰胆碱释放中确定。我们希望在完成这些研究时，表明可替宁具有与人类疾病相关的可开发的治疗潜力，这些疾病的特征是行为和认知障碍以及神经变性。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，可替宁有可能作为一种原型药物，通过它可以比较新药实体。该研究的部分转化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.