Characterization And Pharmacology Of Receptors For Gastrointestinal Peptides

各种胃肠道肽的药理学和分子药理学正在研究中。本年度研究了一个肽受体家族：bombesin- (Bn)相关肽。bn相关肽（GRP， NMB）主要与三种不同的受体（GRP- r, NMB- r）和孤儿受体BRS-3相互作用，介导胃肠道和中枢神经系统（CNS）的一系列作用。在最近的研究中，我们讨论了三种受体的各种类型的激动剂/拮抗剂与人炸弹蛋白受体成员相互作用的能力。我们首先合成了35种不同的合成推定肽拮抗剂，由10种不同的化学类别组成，并检测了它们与人类Bn受体相互作用的能力，这两种细胞系具有单一亚型或Bn- r转染细胞，其受体密度与天然细胞相似。许多种类的高亲和力选择性拮抗剂被确定，这些拮抗剂应该对体内研究有用。一项类似的研究检测了24种天然存在的和合成的氮化硼类似物作为激动剂与这些受体相互作用的能力，并将结果与实验研究中常用的大鼠氮化硼表达细胞的药理学结果进行了比较。结果发现了一些选择性高亲和力的GRP和NMB受体激动剂，并表明大鼠GRP受体药效团与人类的药效团有很大不同，因此不应用于推断人类受体的可能结果。另一项研究考察了NMB对NMB- r的选择性以及Bn对孤儿受体BRS-3的各种合成类似物的分子基础。这些分子决定因素的鉴定将为将来为这些受体开发更具选择性的配体提供信息

The pharmacology and molecular pharmacology of various gastrointestinal (GI) peptides are being investigated. One peptide receptor family was investigated during the year: those for bombesin- (Bn) related peptides. Bn-related peptides (GRP, NMB) interact primarily with three distinct receptors (GRP-R, NMB-R) and the orphan receptor, BRS-3 to mediate a number of effects in the GI tract and central nervous system (CNS). In recent studies we have addressed the ability of various described classes of agonists/antagonists of thee receptors to interact with human bombesin receptor members. We first synthesized 35 different synthetic putative peptide antagonists composed of 10 different chemical classes and examined their abilities to interact with human Bn receptors on both cell lines possessing a single subtype or Bn-R transfected cells containing receptor densities similar to seen on native cells. A number of classes of high affinity selective antagonists were identified which should be useful for in vivo studies. A similar study examined the ability of 24 natural occurring and synthetic Bn analogues to interact with these receptors as agonists and compared the results to the pharmacology in rat Bn expressing cells, which are commonly used in experimental studies. The results identified a number of selective high affinity agonists for the GRP and NMB receptor and showed that the rat GRP receptor pharmacophore differs substantially from that of the human and thus should not be used for extrapolating possible results to human receptors. Another study examined the molecular basis for selectivity of NMB for the NMB-R and of various synthetic analogues of Bn for the orphan receptor, BRS-3. The identification of these molecular determinants will provide information that may allow development of even more selective ligands for these receptors in the future