TY - JOUR
T1 - Pharmacological profile of FK480, a novel cholecystokinin type-A receptor antagonist
T2 - Comparison to loxiglumide
AU - Ito, H.
AU - Sogabe, H.
AU - Nakarai, T.
AU - Sato, Y.
AU - Tomoi, M.
AU - Kadowaki, M.
AU - Matsuo, M.
AU - Tokoro, K.
AU - Yoshida, K.
PY - 1994
Y1 - 1994
N2 - 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 μM, indicating less affinity to central receptors. Intravenous administration of FK480 (ED50 = 18 μg/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 μg/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.
AB - 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 μM, indicating less affinity to central receptors. Intravenous administration of FK480 (ED50 = 18 μg/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 μg/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.
UR - http://www.scopus.com/inward/record.url?scp=0028205914&partnerID=8YFLogxK
U2 - 10.1016/s0022-3565(25)38927-5
DO - 10.1016/s0022-3565(25)38927-5
M3 - 学術論文
C2 - 7509389
AN - SCOPUS:0028205914
SN - 0022-3565
VL - 268
SP - 571
EP - 575
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -