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首页> 外文期刊>CNS drug reviews >ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders.
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ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders.

机译：ABT-089：神经元烟碱型乙酰胆碱受体激动剂的药理性质，可用于治疗认知障碍。

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ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the alpha4beta2 receptor subtype as compared to the alpha-bungarotoxin (alpha-BgT) binding sites on the alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT-089 is as potent and efficacious as (-)-nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT-089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT-089 shows little propensity to induce adverse effects such as ataxia, hypothermia, seizures, cardiovascular or gastrointestinal side effects. Together these data suggest that ABT-089 is a NNR modulator with the potential for treating cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects.
机译：ABT-089 [2-甲基-3-（2-（S）-吡咯烷基甲氧基）吡啶二盐酸盐]是一种选择性神经元烟碱样受体（NNR）调节剂，在认知功能的动物模型中具有认知增强特性。在NNR亚型中，ABT-089与在alpha7和alpha1beta1deltagamma受体亚型上的α-真菌毒素（alpha-BgT）结合位点相比，对alpha4beta2受体亚型上的胱氨酸结合位点具有选择性。在功能性体外电生理和阳离子通量测定中，取决于NNR亚型和测定，ABT-089显示出不同的活性，包括激动，部分激动和拮抗作用。 ABT-089与（-）-尼古丁在诱发从海马突触体释放乙酰胆碱（ACh）时一样有效。此外，ABT-089对兴奋性谷氨酸损伤具有神经保护作用，经过长期治疗后，其效力甚至更高。同样，ABT-089在认知功能模型中也很有效，包括增强基线功能以及改善间隔损伤和自然衰老后出现的认知功能受损。在神经保护测定中，通过长期给药该化合物最有效。与认知模型中的积极作用形成鲜明对比的是，ABT-089几乎没有引起不良反应的倾向，例如共济失调，体温过低，癫痫发作，心血管或胃肠道副作用。这些数据共同表明，ABT-089是一种NNR调节剂，具有治疗认知障碍的潜力，其心血管和胃肠道不良副作用明显有限。

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