Chemistry/Biochemistry/Pharmacology Core

研究及相关-其他项目信息-项目摘要/摘要 这个核心B设施将作为一个技术和科学支助单位，为以下三个项目(1、2、3)提供支持 计划项目拨款。它的主要目标包括：(1)化合物的重新合成和放大 数量，以满足参与项目的研究实验室的体外和体内需求； 测试所有新的邻位配体对CB1和CB2大麻受体的亲和力；(3)测试 与CB1和CB2不可逆/紧密结合的能力；(4)测定官能团 CAMP分析中初始配基的性质(包括正构和变构)；(5)二氨基苯甲酰胺的测试 类似物作为内源性大麻失活酶FAAH的底物；(6) 用肝微粒体和血浆制剂测定配体的代谢和血浆稳定性， 分别；(7)筛选针对G蛋白偶联受体的广泛的靶外相互作用，离子 通道、运输蛋白以及内源性大麻素代谢酶；以及(8)对选定的 一组新的配体在小鼠的中枢和血浆中的生物利用度；每一类的最佳候选者 广泛的药动学图谱。在核心B的支持下生产的化合物也将被 可供本计划项目中确定的其他实验室使用，这些实验室的合作不需要支付赠款费用。

RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT This Core B facility will serve as a technical and scientific support unit for the three Projects (1, 2, 3) of this Program Project Grant. Its major goals involve: (1) the re-synthesis and scale-up of compounds in sufficient quantities to address the in vitro and in vivo needs of the research laboratories involved in the projects; (2) the testing of all new orthosteric ligands for their affinities for the CB1 and CB2 cannabinoid receptors; (3) the testing of orthosteric ligands for their abilities to bind irreversibly/tightly to CB1 and CB2; (4) determining the functional properties of ligands initially in the cAMP assay (both orthosteric and allosteric); (5) the testing of anandamide analogs for their abilities to act as substrates of the endocannabinoid deactivating enzyme, FAAH; (6) determining the metabolic and plasma stabilities of ligands using liver microsomal and plasma preparations, respectively; (7) screening for off-target interactions against a broad panel of G protein-coupled receptors, ion channels, transport proteins as well as endocannabinoid metabolizing enzymes; and (8) evaluation of a select group of novel ligands in mice for their bioavailability in CNS and plasma; the top candidates of each class in an extensive pharmacokinetic profiling. Compounds produced under the auspices of Core B will also be made available to other laboratories identified in this Program Project whose collaboration is at no cost to the grant.