Combinatorial and in situ Approachies to Lead and Refined Compounds

在之前的资助期内，首次发现了GABAB受体的小分子正调节剂，并且发现正调节剂是一种可行的策略，可以在动物模型中逆转与尼古丁依赖相关的行为，同时最大限度地减少不必要的副作用。通过这一应用，我们寻求资源继续开发GABA{B}受体阳性调节剂，并进一步了解其作用机制。项目1的目标是完成现有的以嘧啶为基础的化合物的改进，并找到具有更好性质的替代结构。在一个

In the previous funding period, the first small-molecule positive modulators of the GABAB receptor were discovered, and positive modulation was found to be a viable strategy for reversing behaviors with relevance to nicotine dependence in animal models, while minimizing undesired side-effects. With this application, we seek the resources to continue the development of GABA{B} receptor positive modulators and learn more about their mechanism of action. The goals of Project 1 are to complete the refinement of the existing pyrimidine-based compounds and to find alternative structures with even better properties. Guided by a detailed structure-activity study, modifications certain key positions of the pyrimidine structure are proposed to increase solubility while retaining affinity. We will also mount a parallel effort to generate new lead structures by replacing the central pyrimidine ring with heterocycles that display functional groups in similar orientations. In all cases, the synthetic routes are short, high-yielding, and tolerant of diverse functionality, in order to make it easy to optimize lead structures. Two additional lines of discovery will also be pursued. The first takes advantage of the large compound collection at Scripps Florida, which will be mined by similarity modeling to successful positive modulator structures in Project 2. The resulting candidates will be screened and new leads will be incorporated into the synthesis and testing cycle of Project 1. In addition, we will employ the technique of target-guided synthesis to convert the positive modulators already developed in this program into two-site binders to the GABA{B} receptor. This approach uses a highly selective connecting reaction to join small molecules only when simultaneously bound to adjacent sites on the target protein, giving rise to bivalent ligands of high affinity and selectivity. All new compounds will be screened by a receptor binding assay in the Finn laboratory and by second messenger and signaling assays in Project 2. By close collaboration with the in vitro testing, in vivo pharmacology, and bioinformatics capabilities of Project 2, the best compounds will be identified and refined to arrive at optimized structures for behavioral studies in animal models of nicotine dependence in Project 3.