Synthesis and biological evaluation of cholecystokinin analogs in which the Asp-Phe-NH2 moiety has been replaced by a 3-amino-7-phenylheptanoic acid or a 3-amino-6-(phenyloxy)hexanoic acid

Boc-Tyr(SO 3 H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester (JMV180), an analog of the C-terminal octapeptide of cholecystokinin (CCK-8), shows interesting biological activities behaving as an agonist at the high-affinity CCK binding sites and as an antagonist at the low-affinity CCK binding sites in rat pancreatic acini. Although we did not observe any major hydrolysis of the ester bond of this compound (JMV180) in our in vitro studies, we were aware of a possible and rapid cleavage of this ester bond during in vivo studies. To improve the stability of this compound (JMV180), we decided to synthesize analogs in which the ester bond would be replaced by a carba (CH 2 -CH 2 ) linkage. We synthesized the 3-amino-7-phenylheptanoic acid (β-homo-Aph) with the R configuration in order to mimic the Asp-2-phenylethyl ester poiety and the 3-amino-6-(phenyloxy)hexanoic acid (H-β-homo-App-OH), an analog of H-β-homo-Aph-OH in which a methylene group has been replaced by an oxygen. These compounds were introduced in the CCK-8 sequence and were able to recognize the CCK receptor on rat pancreatic acini, on brain membranes. These analogs might be more suitable for in vivo studies than the first compound (JMV180)