Identification of Novel ACTH small molecule Antagonists

描述（由申请人提供）：肾上腺激素（包括皮质醇和雄激素）的产生受垂体ACTH（促肾上腺皮质激素）的调节，ACTH通过黑素皮质素-2受体（MC2R）刺激类固醇的产生。抗ACTH作用的能力将极大地促进几种临床疾病的护理，包括先天性肾上腺增生和库欣病，这些疾病会影响肾上腺。然而，目前还没有ACTH拮抗剂可用。因此，本提案的具体目的是发现新的MC2R小分子阻滞剂，并将其开发成治疗上述疾病的药物。

DESCRIPTION (provided by applicant): The production of adrenal gland hormones, including cortisol and androgens, is regulated by pituitary ACTH (adrenocorticotropin hormone), which acts via the melanocortin-2 receptor (MC2R) to stimulate steroid production. The ability to antagonize ACTH action would greatly facilitate the care of several clinical conditions, including congenital adrenal hyperplasia and Cushings Disease, which affect the adrenal gland. Yet, ACTH antagonists are not currently available. Thus the specific aim of this proposal is to discover new small molecule blockers of the MC2R with the long-term goal to develop them into drugs to treat the diseases mentioned above. For the purpose of this proposal, we will use Artificial Neural Networks and Support Vector Machines classification methods to design and synthesize targeted drug discovery library of potential ligands for peptide binding G-protein coupled receptors (GPCR), like MC2R. As a screening assay system, we have developed a dual expression sensor cell line, which simultaneously expresses MC2R and GFP-beta-Arrestin fusion protein. Upon the receptor stimulation with ACTH, the MC2R-GFP-beta-Arrestin complex migrates into endosomes. The process can be visualized and quantified with a fluorescent microscopy. In the presence of the receptor inhibition, we expect that the MC2R-GFP-beta-Arrestin complex will be prevented, which will allow for initial hit selection. The hits found will be entered into follow up investigation using both receptor binding techniques to characterize their affinities on membrane preparations containing the MC2R and functional cell responses, cAMP accumulation, to characterize their potencies and efficacies. These studies will involve the combined efforts of Chemical Diversity Labs, Inc., which has expertise in drug discovery chemistry, and a Yale University laboratory with expertise in GPCR action and the treatment of adrenal disorders.