Dengler Daniela G, Harikumar Kaleeckal G, Yen Alice, Sergienko Eduard A, Miller Laurence J
Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, USA.
Membranes (Basel). 2023 Jan 24;13(2):150. doi: 10.3390/membranes13020150.
As part of an ongoing effort to develop a drug targeting the type 1 cholecystokinin receptor (CCK1R) to help prevent and/or treat obesity, we recently performed a high throughput screening effort of small molecules seeking candidates that enhanced the action of the natural agonist, CCK, thus acting as positive allosteric modulators without exhibiting intrinsic agonist action. Such probes would be expected to act in a temporally finite way to enhance CCK action to induce satiety during and after a meal and potentially even modulate activity at the CCK1R in a high cholesterol environment present in some obese patients. The current work focuses on the best scaffold, representing tetracyclic molecules identified through high throughput screening we previously reported. Extensive characterization of the two top "hits" from the previous effort demonstrated them to fulfill the desired pharmacologic profile. We undertook analog-by-catalog expansion of this scaffold using 65 commercially available analogs. In this effort, we were able to eliminate an off-target effect observed for this scaffold while retaining its activity as a positive allosteric modulator of CCK1R in both normal and high cholesterol membrane environments. These insights should be useful in the rational medicinal chemical enhancement of this scaffold and in the future development of candidates to advance to pre-clinical proof-of-concept and to clinical trials.
作为开发一种靶向1型胆囊收缩素受体（CCK1R）以帮助预防和/或治疗肥胖症的持续努力的一部分，我们最近对小分子进行了高通量筛选，寻找能够增强天然激动剂CCK作用的候选物，从而作为正变构调节剂而不表现出内在激动剂作用。预计此类探针将以时间有限的方式发挥作用，增强CCK作用，在进餐期间和进餐后诱导饱腹感，甚至可能在一些肥胖患者存在的高胆固醇环境中调节CCK1R的活性。目前的工作集中在最佳支架上，该支架代表我们先前报道的通过高通量筛选鉴定出的四环分子。对先前研究中两个顶级“命中”物进行的广泛表征表明它们符合所需的药理学特征。我们使用65种市售类似物对该支架进行了类似物目录扩展。在此过程中，我们能够消除该支架观察到的脱靶效应，同时在正常和高胆固醇膜环境中保留其作为CCK1R正变构调节剂的活性。这些见解应有助于对该支架进行合理的药物化学增强，并有助于未来开发候选物，推进到临床前概念验证和临床试验阶段。
