asperlicin and lorglumide

During the last few years, cholecystokinin (CCK) has emerged as an important hormone. This polypeptide has been located either in peripheral tissues such as the gastro-intestinal tract and the pancreas as well as in the central nervous system. High affinity CCK receptors are divided in two main subtypes: the CCK-A (A for (A for "alimentary") and the CCK-B (B for "brain") receptors. The latters are currently associated with the gastrin receptors. Since CCK is involved in many different biological processes such as gut function, digestive processes, control of feeding behaviour and neurotransmitter release, the therapeutical potential of cholecystokinin receptor ligands seems to be extremely broad and promising. Several families of CCK receptor ligands (peptides, peptidomimetics, peptoids or non-peptides) were prepared during the last twenty years. The main goal of these researches was to improve agonistic or antagonistic potency but also to find selective compounds for a specific CCK receptor subtype. This review presents the recent developments (since 1995) in the chemistry of CCK receptor ligands.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Benzodiazepinones; Humans; Indoles; Keto Acids; Ligands; Meglumine; Peptoids; Proglumide; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Spiro Compounds; Structure-Activity Relationship; Tetragastrin

Topics: Amino Acid Sequence; Animals; Benzodiazepinones; Cholecystokinin; Furans; Indoles; Meglumine; Molecular Sequence Data; Proglumide; Receptors, Cholecystokinin; Sincalide; Thiophenes

The present experiments evaluate in vivo effects of recently described cholecystokinin (CCK) receptor antagonists on rat pancreatic secretion. Pancreaticobiliary secretion was studied after bile duct cannulation in anesthetized rats. After two basal 10-min fractions were selected, secretion was stimulated by intravenous caerulein (0.1-30.0 micrograms/kg) or secretin, and collected for seven further 10-min fractions. Peptide antagonists (CR 1409, CR 1392, and CR 1505) and nonpeptide antagonists (asperlicin and L364,718) were given intravenously 10 min before agonists. Increasing doses of antagonists gradually reduced secretion of protein and enzymes stimulated by submaximal and maximal doses of caerulein. The antagonists did not alter nonstimulated or secretin-stimulated secretion, indicating their specificity for the CCK receptor. Except for proglumide and asperlicin, all antagonists were able to abolish caerulein-stimulated pancreatic secretion, as evaluated by the mean integrated 1-h response to a near-maximal dose of caerulein. The caerulein dose-response curve was gradually shifted to the right by increasing doses of CR 1409, indicating competitive-like kinetics. Inhibition of secretion due to supramaximal doses of caerulein, however, could be reversed by doses of CR 1409 smaller than expected from extrapolating truely competitive kinetics from an in vitro situation to the in vivo situation. The rank order of potency of the compounds to antagonize caerulein-stimulated secretion in vivo agreed with their relative potencies to antagonize caerulein-stimulated amylase secretion from pancreatic acini in vitro as well as with their affinity to bind to peripheral CCK receptors in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amylases; Animals; Benzodiazepinones; Ceruletide; Cholecystokinin; Chymotrypsinogen; Devazepide; Dose-Response Relationship, Drug; Male; Pancreas; Proglumide; Proteins; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Secretin

A new simple mouse assay for the in vivo evaluation of CCK antagonists which is based upon visual determination of the gastric emptying of a charcoal meal is described. CCK-8 (24 micrograms/kg s.c.) but not various other peptide and nonpeptide agents effectively inhibited gastric emptying in this test system. The effect of CCK-8 was antagonized by established peripheral CCK antagonists but not representative agents of various other pharmacological classes. The rank order of potency of the CCK antagonists were: L-364,718 (ED50 = 0.01 mg/kg, i.v.; 0.04 mg/kg, p.o.) greater than Compound 16 (ED50 = 1.5 mg/kg, i.v.; 2.0 mg/kg p.o.) greater than asperlicin (ED50 = 14.8 mg/kg i.v.) greater than proglumide (ED50 = 184 mg/kg i.v.; 890 mg/kg, p.o.). Duration of action studies based upon ED50 values determined at various time intervals after oral administration showed that L-364,718 and proglumide are considerably longer acting than Compound 16. Asperlicin (ED50 greater than 300 mg/kg, p.o.) was ineffective as a CCK antagonist when administered orally. These data provide the first direct comparisons of the in vivo potencies of current CCK antagonists and demonstrate the utility of a new simple mouse assay for the in vivo characterization of peripheral CCK antagonists.

Topics: Administration, Oral; Animals; Benzodiazepinones; Binding, Competitive; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Female; Gastric Emptying; Mice; Proglumide; Sincalide; Time Factors