Vol. 290, Issue 3, 1202-1211, September 1999

Comparative Pharmacology of the Nonpeptide Neuromedin B Receptor Antagonist PD 168368

Richard R. Ryan, Tatsuro Katsuno, Samuel A. Mantey, Tapas K. Pradhan, H. Christian Weber, David H. Coy, James F. Battey and Robert T. Jensen

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (R.R.R., T.K., S.A.M., T.K.P., H.C.W., R.T.J.), and Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders (J.F.B.), National Institutes of Health, Bethesda, Maryland; and Peptide Research Laboratories (D.H.C.), Tulane University, New Orleans, Louisiana

The mammalian peptide neuromedin B (NMB) and its receptor are expressed in a variety of tissues; however, little is definitively established about its physiological actions because of the lack of potent, specific antagonists. Recently, the peptoid PD 168368 was found to be a potent human NMB receptor antagonist. Because it had been shown previously that either synthetic analogs of bombesin (Bn) or other receptor peptoid or receptor antagonists function as an antagonist or agonist depends on animal species and receptor subtype studied, we investigated the pharmacological properties of PD 168368 compared with all currently known Bn receptor subtypes (NMB receptor, gastrin-releasing peptide receptor, Bn receptor subtype 3, and Bn receptor subtype 4) from human, mouse, rat, and frog. In binding studies, PD 168368 had similar high affinities (K_i = 15-45 nM) for NMB receptors from each species examined, 30- to 60-fold lower affinity for gastrin-releasing peptide receptors, and >300-fold lower affinity for Bn receptor subtype 3 or 4. It inhibited NMB binding in a competitive manner. PD 168368 alone did not stimulate increases in either intracellular calcium concentration or [³H]inositol phosphates in any of the cells studied but inhibited NMB-induced responses with equivalent potencies in cells containing NMB receptors. PD 168368 was only minimally soluble in water. When hydroxypropyl--cyclodextrin rather than dimethyl sulfoxide was used as the vehicle, both the affinity and the antagonist potency of PD 168368 were significantly greater. The results demonstrate that PD 168368 is a potent, competitive, and selective antagonist at NMB receptors, with a similar pharmacology across animal species. PD 168368 should prove useful for delineating the biological role of NMB and selectively blocking NMB signaling in bioassays and as a lead for the development of more selective nonpeptide antagonists for the NMB receptor.