In an attempt to produce more powerful (effective) bombesin/GRP receptor antagonists, the d forms of Trp or Trp analog (Tpi) were introduced at position 6 in two pseudononapeptides, Leu13Ψ (CH2NH)Leu14‐bombesin(6‐14) and Leu13Ψ(CH2NH)Phe14 ‐bombesin (6‐14). These antagonists were tested for their ability to inhibit basal and gastrin releasing peptide (GRP) (14‐27)‐induced amylase release from rat pancreatic acini in a superfusion assay. They were also assessed for the inhibition of 125I‐Tyr4 ‐bombesin binding to Swiss 3T3 and small cell lung carcinoma cell line H‐345 and the mitogenic response of Swiss 3T3 cells induced by GRP(14‐27). The peptides, when given alone, did not stimulate amylase secretion, but were able to inhibit gastrin releasing peptide (14‐27)‐induced amylase release. All of the antagonists showed strong binding affinities for Swiss 3T3 and H‐345 cells and suppressed the GRP(14‐27)‐induced increase of [3H]thymidine incorporation into DNA of Swiss 3T3 cells at nanomolar concentrations. Antagonist d‐Tpi6,Leu13Ψ (CH2NH)Leu14‐bombesin (6‐14)(RC‐3095) was slightly more potent in these assays than d‐Trp6,Leu13Ψ (CH2NH)Leu14‐bombesin (6‐14)(RC‐3125). Nevertheless, d‐Trp6 Leu13Ψ (CH2NH)Phe14‐bombesin (6‐14) showed the highest binding affinity for Swiss 3T3 and H345 cells and it was the most potent inhibitor of GRP(14‐27)‐induced amylase secretion. This antagonist RC‐3420 was particularly effective in inhibiting the growth of Swiss 3T3 cells, exhibiting an IC50 value less than 1 nm. Our work indicated that the substitution of d‐Trp and d‐Tpi at position 6 of the pseudononapeptide bombesin analogs (Ψ13‐14), in which the Met14 residue is replaced by Leu or Phe, results in potent bombesin/GRP antagonists with improved in vivo activity.