NPY PEPTIDOMIMETICS--DESIGN, SYNTHESIS AND EVALUATION

神经肽Y(NPY)，一种36个氨基酸的多肽类神经递质 与胰腺的内分泌激素具有序列同源性 多肽和PYY家族，被认为折叠成紧凑的， 溶液中的球状结构。在早期的研究中，我们发现 NPY受体拮抗剂苯外明(1)的化学基础 与NPY药效团模型相似。此外，我们还合成了 SC3117(2)、SC3199(3)和CC2137(4)作为NPY官能团模拟物 并将其鉴定为弱到强的Y(2)选择性NPY受体 大鼠股动脉中的拮抗剂。这项建议延伸到我们的 神经肽Y受体非肽拮抗剂的合理设计与应用 关于苯法拉明是一个模拟的官能团的假设 NPY药效团。首先，我们建议对NPY进行直接测试 构象受限类似物合成的结构模型 多肽激动剂NPY(13-36)和NPY。构象 这些多肽的性质将通过圆二色谱和 (1)核磁共振氢谱。第二，我们建议对NPY进行SAR研究 官能团模拟2-4。我们将测试 Y(2)受体选择性的化学和结构特征 和效力：一)立体化学，二)“外层”胺，三) 碱度对胍类化合物氢键性质的影响，以及iv) 对称性。这些NPY受体的第三代拮抗剂 是为了增加它们的膜隔板而设计的 性质、效力和选择性。第三，我们概述了一种方法，以 Y(1)选择性多肽类药物的设计。这些都是适当的 取代的苯二氮卓类药物试图模拟构象 在多肽激动剂中赋予Y(1)选择性的限制。每个人 这些NPY的多肽和非肽类似物将进行测试 受体结合力、内源性活性与竞争性拮抗剂 具有同质受体群体的组织中的活性 Y(1)和Y(2)NPY受体的代表及其变异型 在具有不同NPY受体群体的组织中 这些都是生理上相关的NPY在体内的活动。这些NPY 受体拮抗剂具有相关性，可作为阐明IN的工具 NPY在外周和中枢神经系统中的活体作用，以及AS 药物(或开发药物的适当线索) 治疗心血管疾病和饮食失调，包括 肥胖、神经性厌食症和暴食症。

Neuropeptide Y (NPY), a thirty-six amino acid peptide neurotransmitter with sequence homologies to the endocrine hormones of the pancreatic polypeptide and PYY families, is thought to fold into a compact, globular structure in solution. In earlier studies we identified benextramine (1) as an NPY receptor antagonist based on its chemical similarities to a NPY pharmacophore model. In addition, we synthesized SC3117 (2), SC3199 (3) and CC2137 (4) as NPY functional group mimetics and characterized them as mild to potent, Y(2)-selective NPY receptor antagonists in the rat femoral artery. This proposal extends on our rational design of NPY receptor non-peptide antagonists and is based on the hypothesis that benextramine is a functional group mimetic of the NPY pharmacophore. First, we propose a direct test for the NPY structural model by synthesis of conformationally restricted analogs of the peptide agonists NPY(13-36) and NPY. The conformational properties of these peptides will be assessed by circular dichroism and (1)H-NMR spectroscopy. Second, we propose SAR studies on the NPY functional group mimetics 2-4. We will test the contribution of the following chemical and structural features to Y(2)-receptor selectivity and potency: i) stereochemistry, ii) the "outer" amines, iii) the basicity versus hydrogen bonding properties of the guanidines, and iv) symmetry. These third generation antagonists of the NPY receptor have been designed with regards to increasing their membrane partition properties, potency and selectivity. Third, we outline an approach to the design of Y(1)-selective peptidomimetics. These appropriately substituted benzodiazepines attempt to mimic the conformation restriction which in peptide agonists confer Y(1)-selectivity. Each of these peptide and non-peptide analogs of NPY will be tested for receptor binding potency, intrinsic activity and competitive antagonist activity in tissues with homogeneous receptor populations representative of the Y(1) and Y(2) NPY receptors and the variant types of each, and in tissues with heterogeneous NPY receptor populations that are physiologically relevant NPY's in vivo activities. These NPY receptor antagonists have relevance as tools for elucidating the in vivo role of NPY in the peripheral and central nervous systems, and as drugs (or appropriate leads for the development of drugs) for the treatment of cardiovascular disease and eating disorders, including obesity, anorexia nervosa, and bulimia.