Elimination of a cholecystokinin receptor agonist 'trigger' in an effort to develop positive allosteric modulators without intrinsic agonist activity
Elimination of a cholecystokinin receptor agonist 'trigger' in an effort to develop positive allosteric modulators without intrinsic agonist activity
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DOI：
10.1016/j.bmcl.2015.03.051
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发表时间：
2015-05-01
影响因子：
2.7
通讯作者：
Miller, Laurence J.
中科院分区：
文献类型：
--
作者：
Desai, Aditya J.;Henke, Brad R.;Miller, Laurence J.
胆囊收缩素（CCK）作用于1型胆囊收缩素受体（CCK 1 R），引起饱腹感，是公认的肥胖症药物靶点。迄今为止，已经开发了小分子激动剂，但未能在临床试验中证明足够的功效，并且对副作用和潜在毒性的担忧限制了完全激动剂的进一步开发。使用没有内在激动剂活性的正变构调节剂（PAM）可能是一种更安全的替代方案，这种调节剂仅在餐后短时间内有活性。在这里，我们提出了一种可能的新策略，通过修改现有的小分子激动剂的激动剂“触发器”来开发这样的化合物。我们已经研究了类似物的1，5-苯并二氮卓类激动剂，GI 181771 X，其中N1-异丙基激动剂'触发器'被修改。虽然这些化合物的激动剂活性大大降低，但它们起负调节剂的作用，而不是正调节剂。还发现母体药物对CCK作用无正调节作用。受体结构-活性关系研究表明，这些衍生物的对接模式与母体化合物不同，这可能解释了它们作为负变构调节剂的作用。我们的结论是，这种结果可能是父母激动剂的特点，这种策略可能会更成功地利用父母ago-PAM，具有内在的积极调节活性。(C)2015爱思唯尔有限公司版权所有。
Cholecystokinin (CCK) acts at the type 1 cholecystokinin receptor (CCK1R) to elicit satiety and is a well-established drug target for obesity. To date, small molecule agonists have been developed, but have failed to demonstrate adequate efficacy in clinical trials, and concerns about side effects and potential toxicity have limited further development of full agonists. The use of positive allosteric modulators (PAMs) without intrinsic agonist activity that are active only for a brief period of time after a meal might represent a safer alternative. Here, we propose a possible novel strategy to develop such compounds by modifying the agonist 'trigger' of an existing small molecule agonist. We have studied analogues of the 1,5-benzodiazepine agonist, GI181771X, in which the N1-isopropyl agonist 'trigger' was modified. While agonist activity was greatly reduced in these compounds, they acted as negative, rather than positive modulators. The parent drug was also found to exhibit no positive modulation of CCK action. Receptor structure-activity relationship studies demonstrated that the mode of docking these derivatives was distinct from that of the parent compound, perhaps explaining their action as negative allosteric modulators. We conclude that this outcome is likely characteristic of the parental agonist, and that this strategy may be more successfully utilized with a parental ago-PAM, possessing intrinsic positive modulatory activity. (C) 2015 Elsevier Ltd. All rights reserved.