title: Pharmacological profile of FK480, a novel cholecystokinin type-A receptor antagonist: comparison to loxiglumide.
abstract: The pharmacological profile of FK480[(S)-(+)-N-<1-(2)-fluorophenyl)-3,4,6,7-tetra hydro-4-oxo-pyrrolo(3,2,1-jk) (1,4)benzodiaze-pine-3-yl>-1H-indole-2- carboxamide], a novel cholecystokinin type-A (CCK-A) receptor antagonist, was compared with that of the CCK-A receptor antagonist, loxiglumide. Both FK480 and loxiglumide inhibited 125I-labeled CCK-8 (125I-CCK-8) binding to rat pancreatic and guinea-pig gallbladder membranes with IC50 values of 0.40 +/- 0.04 and 0.06 +/- 0.02 nM for FK480 and 330 +/- 66 and 66 +/- 10 nM for loxiglumide, respectively. These two agents also inhibited 125I-CCK-8 binding to guinea-pig brain (cerebral cortex) receptors with respective IC50 values of 72 +/- 11 nM and > 10 microM, indicating less affinity to central receptors. Intravenous administration of FK480 (ED50 = 18 micrograms/kg) was 2800 times more potent than that of loxiglumide (ED50 = 50 mg/kg) in inhibiting CCK-8-induced pancreatic amylase secretion in rats. Furthermore, FK480 had ED50 values of 10 and 8.4 micrograms/kg, respectively, in antagonizing CCK-8-induced inhibition of charcoal meal gastric emptying in mice when administered orally 1 or 5 hr before the CCK-8. Loxiglumide (ED50 = 23.5 mg/kg, when administered orally 1 hr before the CCK-8) also antagonized it, but its activity was 2400 times less than that of FK480. We conclude that FK480 is a potent, orally effective CCK-A receptor antagonist with long duration of action.
authors.affiliation: Department of Pharmacology, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Sogabe
authors.forename: T
authors.initials: T
authors.lastname: Nakarai
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: M
authors.initials: M
authors.lastname: Tomoi
authors.forename: M
authors.initials: M
authors.lastname: Kadowaki
authors.forename: M
authors.initials: M
authors.lastname: Matsuo
authors.forename: K
authors.initials: K
authors.lastname: Tokoro
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012844:Sincalide / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D007211:Indoles; D011949:Receptors, Cholecystokinin; C082966:FR 120480; C053737:loxiglumide; D000681:Amylases; D011377:Proglumide; D012844:Sincalide