title: Characterization of novel peptoid agonists for the CCK-A receptor.
abstract: The successful design of peptoid CCK-B receptor antagonists using rational approaches suggested that it might be feasible to develop similar non-peptide small molecule agonists with potential therapeutic applications. We now report the characterization of such a compound with full agonist activity at CCK-A receptors on rat exocrine pancreatic acinar cells. The compound, PD149164, stimulated a similar maximal response to CCK8 from the exocrine pancreas in anaesthetized rats in vivo, and from isolated pancreatic acini in vitro it also generated intracellular Ca2+ oscillations similar to those evoked by CCK8. These effects were inhibited by the CCK-A antagonist L-364,718. Interestingly, the enantiomer of PD149164, PD151932, was a CCK-A antagonist and blocked PD149164 stimulated effects on the exocrine pancreas. The data indicate that it is possible to develop both agonist and antagonist activities in enantiomers of small non-peptide molecules.
authors.affiliation: Physiological Laboratory, University of Liverpool, UK.
authors.forename: J
authors.initials: J
authors.lastname: Hughes
authors.forename: G J
authors.initials: GJ
authors.lastname: Dockray
authors.forename: D
authors.initials: D
authors.lastname: Hill
authors.forename: L
authors.initials: L
authors.lastname: Garcia
authors.forename: M C
authors.initials: MC
authors.lastname: Pritchard
authors.forename: E
authors.initials: E
authors.lastname: Forster
authors.forename: E
authors.initials: E
authors.lastname: Toescu
authors.forename: G
authors.initials: G
authors.lastname: Woodruff
authors.forename: D C
authors.initials: DC
authors.lastname: Horwell
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000378:metabolism; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D008536:Meglumine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D010179:Pancreas / Q000378:metabolism; D034444:Peptoids; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; D007211:Indoles; C103206:PD 135154; C102662:PD 140548; C103205:PD 149164; D034444:Peptoids; D010627:Phenethylamines; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C077645:PD 136450; D008536:Meglumine; D000681:Amylases; D000218:Adamantane; D002118:Calcium