Identification of Bombesin Receptor Subtype-Specific Ligands:Effect of N-Methyl Scanning,Truncation,Substitution,and Evaluation of Putative Reported Selective Ligands

摘要

Mammalian bombesin(Bn)receptors include the gastrin-re-leasing peptide receptor,neuromedin B receptor,and bombesin receptor subtype 3(BRS-3).These receptors are involved in a variety of physiological/pathologic processes,including thermoregulation,secretion,motility,chemotaxis,and mito-genic effects on both normal and malignant cells.Tumors frequently overexpress these receptors,and their presence is now used for imaging and receptor-mediated cytotoxicity.For these reasons,there is an increased need to develop synthetic,selective receptor subtype-specific ligands,especially agonists for these receptors.In this study,we used a number of strategies to identify useful receptor subtype-selective ligands,including synthesizing new analogs(N-methyl-substituted constrained analogs,truncations,and substitutions)in [D-Tyr~6,beta Ala~(11),Phe~(13),Nle~(14)]Bn(6-14),which has high affinity for all Bn receptors and is metabolically stable,as well as completely pharmacologically characterized analogs recently reported to be selective for these receptors in [Ca~(2+)]_i assays.Affinities and potencies of each analog were determined for each human Bn receptor subtype.N-Methyl substitutions in positions 14,12,11,10,9,and 8 did not result in selective analogs,with the exception of position 11,which markedly decreased affinity/potency.N-Terminal truncations or position 12 substitutions did not increase selectivity as previously reported by others.Of the four shortened analogs of [D-Phe~6,beta Ala~(11),Phe~(13),Nle~(14)]Bn(6-14)reported to be potent selective BRS-3 ligands on [Ca~(2+)]_i assays,only Ac-Phe,Trp,Ala,His(tau Bzl),Nip,Gly,Arg-NH_2 had moderate selectivity for hBRS-3;however,it was less selective than previously reported Apa~(11)analogs,demonstrating these are still the most selective BRS-3 analogs available.However,both of these analogs should be useful templates to develop more selective BRS-3 ligands.