PD-165929

In this paper we describe the development of a novel series of non-peptide, "balanced" neuromedin-B preferring (BB1)/gastrin-releasing peptide preferring (BB2) receptor ligands as exemplified by PD 176252. PD 176252, which exhibits nanomolar affinity for both the BB1 (Ki = 0.15 nM) and BB2 (Ki = 1.0 nM) receptors, has been demonstrated to be a competitive antagonist at these bombesin receptor subtypes.

A chimeric receptor strategy was used to determination which receptor regions are involved in agonist and antagonist binding at human neuromedin B (NMB) and gastrin-releasing peptide (GRP) receptors.Transmembrane region (TM) V was implicated as a major contributor in the binding of NMB at NMB receptors and as important in the binding of neuromedin C at GRP receptors.Thus, residues divergent between GRP receptors and NMB receptors in these regions may confer ligand selectivity.The antagonist PD 16529 appears to act at the same sites.[D-Phe⁶,des-Met¹⁴]bombesin 6-14 ethylamide binds at completely different regions of the receptor (around TM's I, II and VII) suggesting different antagonistic mechanisms.