Among the CCK derivatives, the tetrapeptide Boc-Trp-Phg-Asp-Nal-NH 2 (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 CONH 2 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 NalNH 2 on the C-terminal part decreased the CCK-B receptor binding affinity. In the series of N-protected tetrapeptides X 30-Phg 31-Asp 32-Nal 33-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 = αMeTrp, 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(CH 3) 2 and 16: 2Adoc- d-αMeTrp-Phg-Asp-NalNH 2 had the best CCK-B receptor affinities ( K 1 = 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 CCK 8 in CHO cells transfected with the rat CCK-B receptor, compound 13 behaved as a full CCK-B antagonist with an IC 50 value of 18 ± 1 nM, being as potent as the antagonists L-365,260 and PD-134,308 (IC 50 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 ( EC 50 = 12 nmol/kg) in anesthetized rats. Compound 13 in contrast, was found to inhibit the pentagastrin action at a dose ( ID 50 = 0.56 μmol/kg) similar to the potent antagonist PD-134,308 ( ID 50 = 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-CCK 4 derivatives presented here. Pseudopeptides derived from CCK4 have been synthesized by liquid phase synthesis. Among these peptides, 2Adoc- d-αMeTrp-Phg-Asp-Nal-NH 2 presents a CCK-B agonist profile, while 2Adoc- d-αMeTrp-Phg-Asp-Nal-N(CH 3) 2 behaves as a very potent CCK-B antagonist. This study emphasizes the role of the N- and C-terminal amino acid substituents on the pharmacological profile of these peptides.