Molecular analysis of antilipemic effects of FR218944, a novel vasopressin V1a receptor antagonist,in genetically diabetic db/db mice in comparison with pioglitazone and fenofibrate

Arginine vasopressin V1a receptor is highly expressed in liver. The aim of this article is to perform a molecular analysis of the effects of a novel nonpeptide V1a receptor (V1aR) antagonist, FR218944 (2‐methoxy‐N‐(2‐methyl‐1H‐benzimidazol‐4‐yl)‐4‐(2,3,4,5‐tetrahydro‐1H‐1‐benzazepin‐1‐yl‐carbonyl)benzamide methanesulfonate), on plasma glucose (Glu) and triglyceride (TG) levels in diabetic db/db mice in comparison with those of a peroxisome proliferator‐activated receptor γ (PPARγ) agonist, pioglitazone, and a PPARα agonist, fenofibrate. FR218944 significantly lowered the plasma TG level but not plasma Glu level after oral administration at 32 mg/kg twice a day for 2 weeks. On the other hand, 10 mg/kg pioglitazone significantly lowered both TG and Glu levels, and 10 mg/kg fenofibrate significantly lowered only the TG level. Significant weight gain was observed only with pioglitazone treatment. db/db mice had lower levels of hepatic V1aR mRNA than normal +/+ mice. The three compounds lowered the mRNA level further. FR218944 significantly raised mRNA levels of β‐oxidation enzymes, Acyl‐CoA oxidase and bifunctional enzymes (BFE). Pioglitazone significantly increased mRNA levels of all the tested enzymes for β‐oxidation and fatty acid synthesis. Fenofibrate significantly increased mRNA levels of Acyl‐CoA synthase and BFE for β‐oxidation and decreased the mRNA level of sterol regulatory element‐binding protein 1, which transactivates many enzymes for fatty acid synthesis. In conclusion, chronic administration of FR218944, a V1aR antagonist, would lower the plasma TG level by increasing energy consumption via upregulation of β‐oxidation enzymes. Furthermore, the compound expresses its antilipemic effect via a different gene‐regulatory pathway from pioglitazone and fenofibrate. FR218944 has the potential to become a new drug for hyperlipemia. Drug. Dev. Res. 60:241–251, 2003. © 2003 Wiley‐Liss, Inc.