Rationally designed ‘dipeptoid’ analogues of cholecystokinin (CCK): N-terminal structure-affinity relationships of α-methyl-tryptophan derivatives

This paper outlines the synthesis and C-terminal structure-activity relationships (SAR) of a series of α-methyl tryptophanylphenethylamide analogues of the neuropeptide cholecystokinin (CCK). CCK-B and CCK-A receptor binding affinities of these analogues are described and the contributions of the various side chains on the phenethylamide moiety to binding affinity are discussed. Several of the compounds prepared have CCK-B receptor binding affinities similar to that found with the endogenous neuropeptide CCK-26-33 (sulphated) (CCK-B, IC 50 = 0.3 nM) and are highly selective over the CCK-A receptor. Amongst the most potent of the compounds synthesized are [ R -( R ∗ , S ∗ )]-β-[[3-(1 H -indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1 3,7 ]dec-2-yloxy )carbonyl]amino]propyl]amino]benzenebutanoic acid 22 , [ R -( R ∗ , S ∗ )]-[[2-[[3-(1 H -indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1 3,7 ]dec-2-yloxy)carbonyl] amino]propyl]amino]-3-phenylpropyl] thio]acetic acid 28a and [ R -( R ∗ , S ∗ )]-[[2-[[3-(1 H -indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1 3,7 ]dec-2-yloxy) carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetic acid 32 which have CCK-B receptor binding affinities of IC 50 = 0.3, 0.3 and 0.2 nM with CCK-A/B ratios of 220, 700 and 1000, respectively. CCK-B receptor selective ligands, 22, 28a and 32 were also shown to be potent antagonists in blocking pentagastrin-evoked excitation in neurons of the rat hypothalamic ventro-medial nucleus (VMN) with the K e values of 2.8, 23 and 5.9 nM, respectively.