α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties.
α4β2 nicotinic acetylcholine receptor partial agonists with low intrinsic efficacy have antidepressant-like properties.
复制标题
α4β2烟碱乙酰胆碱受体部分激动剂具有较低的内在功效具有抗抑郁样性能。
DOI：
10.1097/fbp.0b013e328347546d
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发表时间：
2011-08
影响因子：
1.6
通讯作者：
Picciotto MR
中科院分区：
文献类型：
--
作者：
Mineur YS;Einstein EB;Seymour PA;Coe JW;O'neill BT;Rollema H;Picciotto MR
先前的研究表明，使用含有β2亚基（β2* nAChRs）的尼古丁乙酰胆碱受体的拮抗剂或部分激动剂治疗可产生抗抑郁样作用。在本研究中，我们对辉瑞公司nAChR发现项目合成的3种具有不同亲和力和功能功效的α4β2* nAChR新化合物进行了抗抑郁疗效的悬尾、强迫游泳和新奇性抑制喂养试验。所有测试的化合物在强迫游泳测试中都降低了不动性，其中一种化合物还降低了尾部悬挂测试中的不动性。所有化合物似乎都影响了它们自己的食物摄入量，其中2种化合物显著减少了家养笼子里的摄食，这就排除了对新奇性抑制摄食试验结果的清晰解释。在这里使用的剂量和时间点上，没有一种化合物改变运动活动。因此，这些化合物的一个子集具有药理和行为特性，证明了烟碱化合物作为治疗情绪障碍的潜力。基于尼古丁的抗抑郁药的进一步发展应侧重于提高nAChR亚型的选择性，以获得一致的抗抑郁性能和可接受的副作用。
Previous studies have suggested that treatment with antagonists or partial agonists of nicotinic acetylcholine receptors containing the β2 subunit (β2* nAChRs) results in antidepressant-like effects. In the current study we tested 3 novel compounds with different affinity and functional efficacy at α4β2* nAChRs, which were synthesized as part of nAChR discovery projects at Pfizer in the tail suspension, forced swim and novelty-suppressed feeding tests of antidepressant efficacy. All compounds tested reduced immobility in the forced swim test and one of the compounds also reduced immobility in the tail suspension test. All the compounds appeared to affect food intake on their own, with 2 compounds reducing feeding significantly in the home cage, precluding a clear interpretation of the results in the novelty-suppressed feeding test. None of the compounds altered locomotor activity at the doses and time points used here. Therefore, a subset of these compounds has pharmacological and behavioral properties that demonstrate the potential of nicotinic compounds as a treatment of mood disorders. Further development of nicotinic-based antidepressants should focus on increasing nAChR subtype selectivity to obtain consistent antidepressant properties with an acceptable side effect profile.