Development of CCK-B antagonists.
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.
Horwell
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Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, UK.
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier; D002540:Cerebral Cortex / Q000378:metabolism; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000737:chemistry; D015195:Drug Design; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008536:Meglumine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012844:Sincalide / Q000031:analogs & derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship
D007211:Indoles; D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C025997:cholecystokinin (27-33); D008536:Meglumine; C044201:cholecystokinin (26-33); D002766:Cholecystokinin; D012844:Sincalide