Characterization And Pharmacology Of Receptors For Gastrointestinal Peptides

主要研究蛙皮素受体家族(GRPR、NMBR、BRS-3)和VIP/PACAP家族的受体药理学和分子药理学。在过去的一年里，我们通过蛙皮素受体家族提供了BRS-3激动剂配体MK-5046以变构方式发挥功能的证据，这是第一次描述这一重要受体家族的变构配体。许多研究人员建议使用蛙皮素受体配体来治疗可能的饱腹感和其他中枢神经系统疾病，但临床试验通常受到配体副作用的限制。与其他受体的其他配体一起，许多研究报告变构 与天然的正构体受体配体相比，配体具有优势，不仅在研究它们的药理作用方面，而且在各种生理/病理生理条件下的作用和可能的治疗用途方面也是如此。变构配体的优势包括特定受体比密切相关的家族成员具有更高的特异性，由于其反应的天花板效应而具有更高的安全性，以及潜在的偏向信号。我们使用直接受体结合研究和细胞激活研究提供了证据，证明该配体正在以变构方式激活该受体。我们还使用了涉及受体嵌合体和突变的分子方法来为这一结论提供支持的直接证据。这些结果正在使用其他受体嵌合体和受体定点突变方法来扩展，以进一步确定MK-5046以及最近为BRS-3和其他两个人类BN受体(GRPR，NMBR)描述的其他各种配体的分子基础。 我们的研究以及文献中的数据被用来更新IUPHARs受体分类和英国药理学杂志2021/2022年药理学简明指南：G蛋白偶联受体(蛙皮素受体部分，委员会主席-RT Jensen)。此外，这些数据还被用来从我们的研究和文献中提供证据，支持详细分析和讨论蛙皮素受体在利用这些受体在中枢神经系统肿瘤中的异位表达的新的靶向治疗方法中可能的治疗作用。此外，对VIP/PACAP家族的受体药理学和信号转导进行了综述，并综述了VIP/PACAP家族在包括头痛(偏头痛等)在内的各种人类疾病的可能治疗方法中的作用和应用的最新进展。以及创伤后应激障碍和药物/酒精/吸烟成瘾，使用我们的数据和关于这个受体家族的文献数据。

During the year the receptor pharmacology and molecular pharmacology of primarily the bombesin receptor family (GRPR, NMBR, BRS-3) and VIP/PACAP family and were investigated. With the bombesin receptor family during the last year we have provided evidence that the BRS-3 agonist ligand, MK--5046, is functioning in an allosteric manner, which is the first time an allosteric ligand has been described for this important family of receptors. The use of bombesin receptor ligands for possible satiety and other CNS disorders has been proposed by numerous investigators, but clinical trials were generally limited by the ligands side-effects. With other ligands for other receptors numerous studies report that allosteric ligands have advantages over the native orthosteric receptor ligands, not only for studying their pharmacology but also their role and possible therapeutic use in various physiological/ pathophysiological conditions. The allosteric ligands advantages include greater specificity for a given receptor over closely related family members, , greater safety because of their ceiling effects seen with their responses, and potential for biased signaling. We provide evidence using both direct receptor binding studies and cell activation studies that this ligand is activating this receptor allosterically. We also used a molecular approach involving receptor chimeras and mutagenesis to provide supportive direct evidence for this conclusion. These results are being extended using other receptor chimeras and receptor site-specific mutagenesis approaches to further define the molecular basis for MK-5046 as well as other various ligands recently described for BRS-3 and the other two human BN receptors(GRPR, NMBR). Data from our studies as well as from the literature was used to update the IUPHARs receptor classification and the British Journal of Pharmacology Concise Guide to Pharmacology 2021/2022:G protein coupled receptors (bombesin receptor section, committee Chair-RT Jensen). In addition, this data was used to provide evidence from both our studies and the literature supporting a detailed analysis and discussion of the possible therapeutic roles for bombesin receptors for novel targeted therapeutic approaches utilizing the ectopic expression of these receptors in CNS/neural tumors. Furthermore, the receptor pharmacology as well as the signaling for the VIP/PACAP family was reviewed and the recent advances reviewed in their role/use in possible therapeutic approaches in various human diseases including the pathogenesis of headaches (migraine, etc.) as well as posttraumatic stress disorder and drug/alcohol/smoking addiction, using both our data and the data from the literature on this receptor family.