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首页> 外文期刊>CNS drug reviews >TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects.
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TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects.

机译：TC-1734：口服活性神经元烟碱型乙酰胆碱受体调节剂，具有抗抑郁，神经保护和持久的认知作用。

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The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia.
机译：靶向神经元烟碱型乙酰胆碱受体以减轻与神经退行性疾病有关的症状的选择性配体的开发具有影响多种缺陷的优势，这些缺陷是这些病理学的标志。 TC-1734是一种对神经元烟碱受体具有高选择性的口服活性新型神经元烟碱激动剂。微透析研究表明，TC-1734可增强乙酰胆碱从皮质的释放。通过急性或反复给药，TC-1734在大鼠和小鼠中显示出增强记忆的特性，并且在培养物中对胎儿大鼠脑进行兴奋性毒性损伤后具有神经保护作用，并能抵抗因海马切片中葡萄糖和氧气的缺乏而引起的突触传递改变。在低于最大剂量时，TC-1734与他克林或多奈哌齐组合使用可产生加性认知作用。与（-）-尼古丁不同，重复施用TC-1734后不会发生行为致敏作用。它的药代动力学（PK）曲线（半衰期为2小时）与工作记忆的长期持久改善（18小时）形成对比，表明认知能力的改善超出了化合物的寿命。 TC-1734的极低急性毒性及其受体活性特征为其潜在的临床候选者提供了进一步的机理基础。在小鼠，大鼠和狗的急性和慢性口服毒性研究中，TC-1734具有很好的耐受性。 I期临床试验表明，急性口服给予TC-1734的药代动力学和安全性良好，剂量范围为2至320 mg。 TC-1734的生物利用度，药理学，药代动力学和安全性概况提供了一个安全，有效和有效的神经元烟碱调节剂的例子，该疗法有望治疗痴呆症中所观察到的典型症状。

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