NOVEL ASP(32)-REPLACEMENT TETRAPEPTIDE ANALOGS AS POTENT AND SELECTIVE CCK-A AGONISTS

A series of novel CCK tetrapeptide analogues of the general formula Bo c-Trp-Lys(Tac)-N(R)-(CH2)(n)CON(R') Phe-NH2 (Tac = o-tolylaminocarbony l), where R, R' = H or Me and n = 1-5, have been synthesized and teste d. These analogues, which lack an acidic residue at the penultimate po sition, demonstrated surprisingly high CCK-A receptor affinity and sel ectivity. The effect of N-methylation pattern on CCK-A receptor affini ty showed consistent trends for analogues in which n = 1, 2, or 3, wit h the di-N-methylated analogues having the highest affinity in each ca se. However, none of these analogues had full agonist activity, as mea sured by percent maximal PI hydrolysis. Two conformationally constrain ed analogues also demonstrated high CCK-A receptor affinity and select ivity, as well as nearly maximal agonist activity. In addition, one of these conformationally-constrained analogues demonstrated anorectic a ctivity in rats.