The pharmacology and molecular pharmacology of various gastrointestinal (GI) peptides are being investigated. One peptide receptor family was investigated during the year: those for bombesin- (Bn) related peptides. 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). Little is known of the pharmacology of various putative antagonists for human receptors with almost all studies performed in nonhuman cells. To address this question we synthesized 35 different synthetic putative peptide antagonists composed of 10 different chemical classes and examined their abilities to interact with human Bn receptors on both cell lines possessing a single subtype or Bn-R transfected cells containing receptor densities similar to seen on native cells. A number of classes of high affinity selective antagonists were identified which should be useful for in vivo studies. Another two studies examined the molecular basis for selectivity of NMB for the NMB-R and of various synthetic analogues of Bn for the orphan receptor, BRS-3. The identification of these molecular determinants will provide information that may allow development of even more selective ligands for these receptors in the future
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