INHIBITORY CYCLIC ANALOGS AND CHLORAMBUCIL DERIVATIVES OF BOMBESIN-LIKE PEPTIDES

Analogues of the amphibian neuropeptide, bombesin, and of the mammalia n homologue, gastrin-releasing peptide, have been synthesized and thei r biological activity studied in small cell lung carcinoma and rat pan creatic acinar cells. The compounds are truncated sequences of the act ive tetradecapeptide BN(1-14) or GRP(20-27). Peptides were cyclized be tween position 5 or 7 and the carboxyl end of the des-Met(14) fragment with D and L Ala(11) and Lys(5) substitutions, as well as various N-t erminal groups attached. The smallest cyclic peptide, BN(7-13), bound to SCLC membranes with mu M potency and inhibited BN stimulation of in tracellular Ca++ levels. The most potent inhibitor is N-chlorambucil-[ His(7),D-Ala(11)]BN(7-13)ethyl ester, which antagonized BN function in SCLC and acinar cells with nM potency and also inhibited clonal growt h of carcinoma cell lines.