Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi

Seven new antagonists of bombesin (Bn)/gastrin-releasing peptide (GRP) containing C-terminal Trp or Tpi (2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-carboxylic acid) in a reduced peptide bond were synthesized by solid phase methods and evaluated biologically. The reduced bond in four [Leu 13ψ(CH 2NH)Trp 14]Bn(6–14) analogs was formed by reductive alkylation at the dipeptide stage. In the case of three [Leu 13ψ(CH 2N)Tpi 14]Bn(6–14) analogs, the Trp dipeptide with reduced bond was reacted with formaldehyde to form the corresponding Tpi derivative. These Tpi-containing analogs have a new reduced bond which is structurally more constrained. Leu 13ψ(CH 2N)Tpi 14 analogs inhibit [ 125I][Tyr 4]bombesin binding to Swiss 3T3 cells with IC 50 values of 2–4 nM, compared to 5–10 nM for Leu 13ψ(CH 2NH)Trp 14 analogs. Leu 13ψ(CH 2N)Tpi 14 analogs are also more potent than Leu 13ψ(CH 2NH)Trp 14 analogs in growth inhibition studies using Swiss 3T3 cells. The two best bombesin antagonists of this series, [D-Trp 6,Leu 13ψ(CH 2N)Tpi 14]Bn(6–14) (RC-3415) and [Tpi 6,Leu 13ψ(CH 2N)Tpi 14]Bn(6–14) (RC-3440), inhibited GRP-stimulated growth of Swiss 3T3 cells with IC 50 values less than 1 nM. RC-3440 was also active in vivo, suppressing GRP(14–27)-stimulated serum gastrin secretion in rats. Bombesin/GRP antagonists, such as RC-3440, containing the new reduced bond (CH 2N) reported herein are very potent.