Characterization And Pharmacology Of Receptors For Gastrointestinal Peptides

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

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.