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Pharmacological profile of FK480, a novel cholecystokinin type-A receptor antagonist: comparison to loxiglumide

H Ito, H Sogabe, T Nakarai, Y Sato, M Tomoi, M Kadowaki, M Matsuo, K Tokoro and K Yoshida

Department of Pharmacology, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.

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.

Volume 268, Issue 2, pp. 571-575, 02/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


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