Characterization And Pharmacology Of Receptors For Gastrointestinal Peptides

在这一年中，主要研究了蛙皮素受体家族（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，我们已经提供了BRS-3激动剂配体MK-5046以变构方式发挥作用的证据，这是第一次描述了这个重要的受体家族的变构配体。蛙皮素受体配体用于可能的饱腹感和其他CNS疾病已被许多研究者提出，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，许多研究报告说， 配体具有优于天然正构受体配体的优点，不仅用于研究它们的药理学，而且用于研究它们在各种生理/病理生理条件下的作用和可能的治疗用途。变构配体的优势包括对给定受体的特异性高于密切相关的家族成员，由于其响应中观察到的天花板效应而具有更高的安全性，以及偏向信号传导的可能性。我们使用直接受体结合研究和细胞活化研究提供证据表明，这种配体激活这种受体变构。我们还使用了一种分子方法，涉及受体嵌合体和诱变，提供支持这一结论的直接证据。这些结果正在使用其他受体嵌合体和受体位点特异性诱变方法进行扩展，以进一步确定MK-5046以及最近描述的BRS-3和其他两种人BN受体（GRPR，NMBR）的其他各种配体的分子基础。 我们的研究以及文献数据用于更新IUPHAR受体分类和英国药理学杂志简明药理学指南2021/2022：G蛋白偶联受体（蛙皮素受体部分，委员会主席-RT詹森）。此外，这些数据被用来提供证据，从我们的研究和文献支持的详细分析和讨论的可能的治疗作用蛙皮素受体的新的靶向治疗方法，利用这些受体在中枢神经系统/神经肿瘤的异位表达。 此外，还综述了VIP/PACAP家族的受体药理学以及信号传导，并综述了其在各种人类疾病（包括头痛（偏头痛等）的发病机制）中的可能治疗方法中的作用/用途的最新进展。以及创伤后应激障碍和药物/酒精/吸烟成瘾，使用我们的数据和来自该受体家族文献的数据。

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.