Role of N- and C-terminal substituents on the CCK-B agonist - Antagonist pharmacological profile of Boc-Trp-Phg-Asp-Nal-NH2 derivatives

Article abstract of DOI:10.1016/0968-0896(96)00050-8

Among the CCK derivatives, the tetrapeptide Boc-Trp-Phg-Asp-Nal-NH₂ (1) behaves as a short potent CCK-B agonist which led to the development of an efficient peptidase-resistant CCK-B antagonist by bismethylation of its terminal CONH₂ group. Further modifications of the N-and C-terminal moieties of 1 have been performed and are described in this paper, together with the pharmacological profile of the novel synthesized compounds. Introduction of more bulky substituents than NalNH₂ on the C-terminal part decreased the CCK-B receptor binding affinity. In the series of N-protected tetrapeptides X³⁰-Phg³¹-Asp³²-Nal³³-N(CH ₃)₂, the Boc-substituent was shown to be optimal among the N-protecting groups Boc, ²Adoc, propionyl or acetyl when X = Trp. On the other hand, when X = αMcTrp, its optimal N-protecting group was ²Adoc and its configuration was preferentially D. In the newly synthesized compounds, 13: ²Adoc-D-αMeTrp-Phg-Asp-NalN(CH₃)₂ and 16: ²Adoc-D-αMeTrp-Phg-Asp-NalNH₂ had the best CCK-B receptor affinities (K₁ = 3.5 and 3.4 nM, respectively) and were selected for further biological evaluation. Interestingly, when tested for their capacity to influence inositol phosphate formation, induced by CCK₈ in CHO cells transfected with the rat CCK-B receptor, compound 13 behaved as a full CCK-B antagonist with an IC₅₀ value of 18 ± 1 nM, being as potent as the antagonists L-365,260 and PD-134,308 (IC₅₀ values respectively, 39 ± 17 and 30 ±2 nM), whereas compound 16 was found to behave as a partial CCK-B agonist. Indeed 16 behaved as an antagonist on the firing rate of rat CA1 hippocampal neurons and acted as an agonist in the pentagastrin stimulated gastric acid secretion (EC₅₀ = 12 nmol/kg) in anesthetized rats. Compound 13 in contrast, was found to inhibit the pentagastrin action at a dose (ID₅₀ = 0.56 μmol/kg) similar to the potent antagonist PD-134,308 (ID₅₀ = 0.4 μmol/kg). The antagonist/agonist properties of compounds 13 and 16 show that both N-and C-terminal substituents modulate the pharmacological properties in the Boc-CCK₄ derivatives presented here. Copyright