Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo
Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo
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DOI：
10.1016/s0091-3057(96)00354-1
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发表时间：
1997-05-01
影响因子：
3.6
通讯作者：
Arneric, SP
中科院分区：
文献类型：
--
作者：
Briggs, CA;Anderson, DJ;Arneric, SP
用人重组烟碱型乙酰胆碱受体(NAChRs)体外药代动力学和行为学模型，研究了与大鼠神经元烟碱型乙酰胆碱受体(NAChRs)相互作用的化合物(2，4)-二甲氧基亚甲基花叶碱二盐酸盐(GTS-21)的药代动力学和行为学。GTS-21与人α4β2 nAChR(K-I=20 nM)的结合力是人α7 nAChR的100倍，分别是人α4β2和α7 nAChR的18倍和2倍。在功能上，GTS-21刺激大鼠纹状体脑片释放[H-3]多巴胺的EC50为10+/-2mU M(效力是(-)-尼古丁的250倍，有效率是(-)-尼古丁的70%)，这种作用可被nAChR拮抗剂二氢β-乙二胺阻断。然而，GTS-21对人α4β2和人神经节细胞nAChRs没有明显的刺激作用。在体内，GTS-21对狗的血压无不良影响(小于或等于2.5mU/kg静脉注射)。推注)，与(-)-尼古丁形成鲜明对比。GTS-21(小于或等于62mU/kg，S.C.)也没有与(-)-尼古丁在大鼠身上有明显的交叉区别，也没有降低小鼠的体温或运动能力。在正常小鼠升高+迷宫焦虑模型(0.19~6.2mU·m o l/kg，ip)中也未见活性。然而，GTS-21确实改善了猴子在延迟匹配到样本任务(32-130mnol/kg，I.M.)中的学习成绩。(C)1997年爱思唯尔科学公司。
(2,4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a compound that interacts with rat neuronal nicotinic acetylcholine receptors (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and monkeys. GTS-21 bound to human alpha 4 beta 2 nAChR (K-i = 20 nM) 100-fold more potently than to human alpha 7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally, GTS-21 stimulated [H-3]dopamine release from rat striatal slices with an EC50 of 10 +/- 2 mu M (250-fold less potent and 70% as efficacious as (-)-nicotine), an effect blocked by the nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect on dog blood pressure (less than or equal to 2.5 mu mol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine. GTS-21 (less than or equal to 62 mu mol/kg, s.c.) also did not cross-discriminate significantly with (-)-nicotine in rats and did not reduce temperature or locomotion in mice. Neither was it active in the elevated plus maze anxiety model (0.19-6.2 mu mol/kg, IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 mnol/kg, i.m.). (C) 1997 Elsevier Science Inc.