During the year the receptor pharmacology and molecular pharmacology of a number of gastrointestinal hormones/ neurotransmitters and growth factors was investigated including members of the PACAP-VIP family, bombesin receptor family, neurotensin family as well as publishing a number of expert opinions of advances in this field. In the case of the PACAP-VIP family of peptides, three receptors mediate their actions (VPAC1, VPAC2, PAC1), however no PAC1 specific ligands exist. This receptor has marked neuroprotective, neuroregenerative effects as well as antifilammotry effects and there is considerable need for a PAC1 selective agonist. In collaboration with Prof David Coy, Tulane University, 46 analogues of PACAP/VIP were synthesized, primary conformationally restricted in areas that are known to be important for agonist activity. A number of analogues were selective more than 80 fold for PAC1 over the VPAC2. These analogues will be important for defining PAC1s role therapeutically and in diseases. In collaboration with Prof M leopoldo 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). The BRS-3 receptor is receiving considerable attention because BRS-3 knockout mice develop obesity, altered metabolism and diabetes, and the receptor has growth effects on some neoplastic tissues. Until recently there were no selective agonists or antagonist to allow assessment of the importance of BRS-3 in various physiological/pathophysiological conditions. With Prof M.Leopoldo, nonpeptide antagonist were identified. for the first time for the BRS-3 receptor. In collaboration with Prof T Ito, Kyushu University, the importance of the GLP1 receptor on pancreatic stellate cells was studied. These cells are important in mediating both aspects of acute and chronic pancreatitis inducing inflammation, fibrosis and cytokine realses, and there is controversy about whether the clinical use of GLP1 R agonists for treatment of diabetes causes the occurrence of pancreatitis. Our collaborate study demonstrates GLP1-R receptors occur on activated pancreatic stellate cells and can induce their growth. This could be a mechanism for GLP-1R inducing pancreatic disease.
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