Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists.
Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists.
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发现芳基磺酰胺作为双重食欲素受体激动剂。
DOI：
10.1021/acs.jmedchem.1c00841
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发表时间：
2021-06-24
影响因子：
7.3
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang D;Perrey DA;Decker AM;Langston TL;Mavanji V;Harris DL;Kotz CM;Zhang Y
产生食欲素的神经元的丧失导致发作性睡病，而在动物模型中，已经显示出具有兴奋性的食欲素激动剂可以增加觉醒并减轻发作性睡病症状。已经报道了几种OX 2 R激动剂，但对OX 1 R几乎没有活性或没有活性。我们对OX 2 R激动剂YNT-185（2）进行了构效关系（SAR）研究，发现了双重激动剂如RTOXA-43（40），对OX 2 R和OX 1 R的EC 50均为24 nM。基于激动剂结合的OX 2 R cryo-EM结构的计算建模研究表明，40结合在相同的结合口袋中，并且40的吡啶基甲基与OX 1 R的相互作用可能有助于其高OX 1 R效力。腹膜内注射40增加了12月龄小鼠的清醒时间，减少了睡眠时间，并增加了睡眠/觉醒巩固。这项工作提供了一个有前途的双重小分子激动剂，并支持开发食欲素激动剂作为食欲素缺乏症，如嗜睡症的潜在治疗。
Loss of orexin-producing neurons results in narcolepsy with cataplexy and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported, but with little or no activity at OX1R. We conducted structure-activity relationship (SAR) studies on OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC50’s of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist bound OX2R cryo-EM structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.
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影响因子：
16.6
作者：
Hong C;Byrne NJ;Zamlynny B;Tummala S;Xiao L;Shipman JM;Partridge AT;Minnick C;Breslin MJ;Rudd MT;Stachel SJ;Rada VL;Kern JC;Armacost KA;Hollingsworth SA;O'Brien JA;Hall DL;McDonald TP;Strickland C;Brooun A;Soisson SM;Hollenstein K
通讯作者：
Hollenstein K
影响因子：
3.4
作者：
Chow M;Cao M
通讯作者：
Cao M
影响因子：
--
作者：
de Lecea, Luis
通讯作者：
de Lecea, Luis
影响因子：
4.6
作者：
Davies J;Chen J;Pink R;Carter D;Saunders N;Sotiriadis G;Bai B;Pan Y;Howlett D;Payne A;Randeva H;Karteris E
通讯作者：
Karteris E
DOI：
10.1073/pnas.0507480102
发表时间：
2005-12-27
影响因子：
11.1
作者：
Boutrel, B;Kenny, PJ;de Lecea, L
通讯作者：
de Lecea, L