MINOR STRUCTURAL DIFFERENCES IN BOC-CCK-4 DERIVATIVES DICTATE AFFINITY AND SELECTIVITY FOR CCK-A AND CCK-B RECEPTORS

We previously reported novel Boc-CCK-4 (Boc-Trp-Met-Asp-Phe-NH2) deriv atives possessing the general structure Boc-Trp-Lys[N-epsilon-CO-NH-(R -Ph)]-Asp-Phe-NH2 (Shiosaki et al. J. Med. Chem. 1991, 34, 2837-2842). In contrast to Boc-CCK-4, which is 70-fold selective for the CCK-B re ceptor, the modified lysine-bearing tetrapeptides were highly potent a nd selective full agonists at the CCK-A receptor. Further investigatio n of the structure-activity profile following modification of the subs tituted phenylurea moiety appended off the lysine revealed that moving certain substituents, e.g. nitro or acetyl, from the 2- or 3-position on the phenyl ring to the 4-position, a relatively minor and subtle s tructural modification within the tetrapeptide, resulted in loss of CC K-A receptor selectivity and development of a trend toward CCK-B selec tivity. These tetrapeptides, e.g. oc-Trp-Lys[N-epsilon-CO-NH-(4-NO2-Ph )]-Asp-Phe-NH2 and oc-Trp-Lys[N-epsilon-CO-NH-(4-Ac-Ph)]-Asp-Phe-NH2, were full agonists relative to CCK-8 in stimulating intracellular calc ium mobilization in a cell line that expresses the, CCK-B receptor.