MODIFICATION OF RECEPTOR SELECTIVITY AND FUNCTIONAL-ACTIVITY IN CHOLECYSTOKININ PEPTOID LIGANDS

Hybrid analogs of the cholecystokinin A (CCK-A) receptor selective tet rapeptide agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (1, A-71623) and the CCK-B receptor selective antagonists PD-135118 (2) and CI-988 (3) were prepared. Incorporation of the Lys(Tac) side chain into 2 produced a moderately potent antagonist of CCK-8 in the isolated guinea pig gallb ladder (GPGB). Incorporation of the Lys(Tac) side chain into 3 produce d the novel agonist analog 7 (EC(50) = 28 nM in the GPGB) with excelle nt affinity for both human CCK-A (IC50 = 12 nM) and CCK-B (IC50 = 17 n M) receptors. Analog 7 was a full agonist (EC(50) = 3.5 nM) for calciu m mobilization on CHO-K1 cells expressing hCCK-A receptors but a parti al agonist on CHO-K1 cells expressing hCCK-B receptors, eliciting a we ak agonist reponse (EC(50) = 2800 nM) and antagonizing CCK-8-induced c alcium mobilization (K-B = 20 nM). Despite this unusual in vitro profi le, analog 7 was a potent anorectic agent in rats (ED(50) = 30 nmol/kg ) following intraperitoneal administration.