Identification and Pharmacological characterization of Bombesin receptor subtype-3 selective agonist

Of all the non-somatosensory G protein-coupled receptors (GPCRs), about 100 are “orphan receptors”: GPCRs whose natural ligands have not yet been identified. Their physiological functions therefore remain obscure and difficult to investigate directly. Bombesin receptor subtype-3 (BRS-3) is an early orphan receptor that has been resistant to “deorphanization”. However, BRS-3 deficient mice have been created and shown to develop a late-onset mild obesity with metabolic defects. This implicates BRS-3 as having a role in regulating feeding and metabolism. In order to search for the physiological function of BRS-3, we first investigated the anatomical distribution of BRS-3 and found that BRS-3 is mostly expressed in the central nervous system. We show that the highest levels of BRS-3 mRNA expression are found in the hypothalamus, in the testis and in the bone marrow. We then screened for BRS-3 selective agonists and found a synthetic small molecule compound which proved to act as a selective high-affinity agonist for BRS-3 and does not activate the other bombesin receptors, the gastrin-releasing peptide- and neuromedin B-receptors. Intracerebroventricular administration of this agonist in rats showed however no effect on normal food intake. It also did not affect locomotor activity. This suggests that the anorexigenic effect of the BRS-3 system might be mediated through a novel mechanism which we are investigating. This work is supported by NIH Grant MH60231, DK63001 and DK70619.