Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats.
Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats.
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DOI：
10.1124/jpet.108.140350
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Lindsley CW
中科院分区：
文献类型：
--
作者：
Brady AE;Jones CK;Bridges TM;Kennedy JP;Thompson AD;Heiman JU;Breininger ML;Gentry PR;Yin H;Jadhav SB;Shirey JK;Conn PJ;Lindsley CW
先前的临床和动物研究表明，M1 和/或 M4 毒蕈碱乙酰胆碱受体 (mAChR) 的选择性激活剂具有作为治疗精神分裂症和阿尔茨海默病的新型治疗剂的潜力。然而，M1 或 M4 的高选择性中枢渗透激活剂尚未可用，因此无法确定这些受体选择性激活的体内效应。我们之前鉴定出 VU10010 [3-氨基-N-(4-氯苄基)-4, 6-二甲基噻吩并[2,3-b]吡啶-2-甲酰胺]是 M4 mAChR 的有效选择性变构增强剂。然而，不利的理化性质阻碍了该化合物用于体内研究。我们现在报告，VU10010 的化学优化提供了两种中心渗透类似物，VU0152099 [3-氨基-N-(苯并[d][1,3]二氧杂环醇-5-基甲基)-4,6-二甲基噻吩并[2,3-b]吡啶甲酰胺]和VU0152100 [3-氨基-N-(4-甲氧基苄基)-4,6-二甲基噻吩并[2,3-b]吡啶甲酰胺]，是 M4 的有效且选择性正变构调节剂。 VU0152099和VU0152100没有激动剂活性，但增强了M4对乙酰胆碱的反应。两种化合物对其他 mAChR 亚型或一组其他 GPCR 均缺乏活性。 VU0152099 和 VU0152100 的理化性质得到改善，可以在大鼠体内给药并评估行为影响。有趣的是，这些 M4 的选择性变构增强剂可逆转安非他明诱导的大鼠过度运动，该模型对已知的抗精神病药物和非选择性 mAChR 激动剂敏感。这与 M4 在调节中脑多巴胺能活性中发挥重要作用的假设是一致的，并提出了 M4 的正变构调节可能模仿选择性较低的 mAChR 激动剂的一些抗精神病样作用的可能性。
Previous clinical and animal studies suggest that selective activators of M1 and/or M4 muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment of schizophrenia and Alzheimer’s disease. However, highly selective centrally penetrant activators of either M1 or M4 have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. We previously identified VU10010 [3-amino-N-(4-chlorobenzyl)-4, 6-dimethylthieno[2,3-b]pyridine-2-carboxamide] as a potent and selective allosteric potentiator of M4 mAChRs. However, unfavorable physiochemical properties prevented use of this compound for in vivo studies. We now report that chemical optimization of VU10010 has afforded two centrally penetrant analogs, VU0152099 [3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide] and VU0152100 [3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide], that are potent and selective positive allosteric modulators of M4. VU0152099 and VU0152100 had no agonist activity but potentiated responses of M4 to acetylcholine. Both compounds were devoid of activity at other mAChR subtypes or at a panel of other GPCRs. The improved physiochemical properties of VU0152099 and VU0152100 allowed in vivo dosing and evaluation of behavioral effects in rats. Interestingly, these selective allosteric potentiators of M4 reverse amphetamine-induced hyperlocomotion in rats, a model that is sensitive to known antipsychotic agents and to nonselective mAChR agonists. This is consistent with the hypothesis that M4 plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M4 may mimic some of the antipsychotic-like effects of less selective mAChR agonists.
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影响因子：
6.1
作者：
Felder, CC;Porter, AC;Wess, J
通讯作者：
Wess, J
影响因子：
17.7
作者：
Shekhar, Anantha;Potter, William Z.;Felder, Christian C.
通讯作者：
Felder, Christian C.
代谢型谷氨酸受体亚型 1 的一类新型正性异构调节剂与一个不同于负性异构调节剂的位点相互作用
影响因子：
3.6
作者：
Hemstapat, Kamondanai;de Paulis, Tomas;Conn, P. Jeffrey
通讯作者：
Conn, P. Jeffrey
DOI：
10.1073/pnas.1835724100
发表时间：
2003-11-11
影响因子：
11.1
作者：
Marino, MJ;Williams, DL;Conn, PJ
通讯作者：
Conn, PJ
一种 M4 mAChR 的异位增效剂可调节海马突触传递
影响因子：
14.8
作者：
Shirey, Jana K.;Xiang, Zixiu;Conn, P. Jeffrey
通讯作者：
Conn, P. Jeffrey