cholecystokinin-(26-33) and cholecystokinin-(27-33)

Our approach to design small molecule non-peptide analogues of the neuropeptide cholecystokinin (CCK) has led to the discovery of the CCK-B antagonist 'dipeptoids'. A representative member of this series of compounds, PD134308 [R-(R*,R*)]-4-[[2-[[3-(1H-Indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl] amino]-1-phenylethyl]amino]-4-oxobutanoic acid has high affinity (Ki = 1.7 nM) and selectivity for the CCK-B receptor (CCK-A/B ratio is 2500:1), is well absorbed and shows robust anxiolytic properties in several anxiogenic models in a dose related manner by both s.c. and oral routes of administration over the dose range 0.1-30 mg/Kg. The rational design of these dipeptoids from CCK 26-33 has involved the identification of the non-contiguous dipeptide fragment of CCK, Boc-Trp-Phe-NH2 with low micromolar affinity in binding assays. This dipeptide has been systematically chemically modified at the N- and C-terminal to increase CCK-B binding affinity 10,000-fold. These modifications include replacement of the L-tryptophan moiety by the non-genetically coded D-alpha-methyltryptophan residue. The modifications also enhance the stability of the molecule towards enzymatic and acid degradation and increase overall lipophilicity compared with the peptide in order to facilitate penetration of the blood-brain barrier.

Topics: Amino Acid Sequence; Animals; Binding Sites; Blood-Brain Barrier; Cerebral Cortex; Cholecystokinin; Drug Design; Indoles; Meglumine; Mice; Molecular Sequence Data; Peptide Fragments; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship

In dispersed acini from guinea pig, mouse, or rat pancreas cholecystokinin-(27-33) is a full agonist, and removing the sulfate ester from the tyrosine residue in position 27 caused a 100- to 300-fold decrease in potency with no change in efficacy. In dispersed acini from mouse or rat pancreas, cholecystokinin-(27-32)-NH2 is a partial agonist, and removing the sulfate ester from the tyrosine in position 27 abolished the efficacy. The desulfated peptide was able, however, to interact with CCK receptors with a potency that was threefold less than that of cholecystokinin-(27-32)-NH2 and therefore functioned as a cholecystokinin receptor antagonist. In dispersed acini from guinea pig pancreas cholecystokinin-(27-32)-NH2 is a cholecystokinin receptor antagonist. Removing the sulfate ester from the tyrosine residue in position 27 of cholecystokinin(27-32)-NH2 caused a fourfold decrease in potency but did not abolish the ability of the peptide to interact with cholecystokinin receptors; therefore, desulfated cholecystokinin-(27-32)-NH2 functioned as a cholecystokinin receptor antagonist.

Topics: Amylases; Animals; Carboxylic Acids; Cholecystokinin; Esters; Guinea Pigs; Male; Mice; Pancreas; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Sincalide; Structure-Activity Relationship; Sulfates