ANTIOBESITY EFFECT OF MPV-1743-A-III, A NOVEL IMIDAZOLINE DERIVATIVE,IN GENETIC OBESITY

MPV-1743 (5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha(2)-adrenoceptor subtypes alpha(2A) (IC50 = 0.66 +/- 0.06 nM), alpha(2B) (IC50 = 3.8 +/- 0.53 nM), alpha(2C) (IC50 = 3.1 /- 0.61 nM) in the recombinant S115 cells and to alpha(2D) (IC50 = 0.9 4, +/- 0.10 nM) in the rat submandibular gland. MPV-1743 AIII also sho wed remarkably high affinity to alpha(1)-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I-2b-binding sit es (IC50 = 150 +/- 5.0 nM) in the rat liver. The functional alpha(2)-a drenoceptor antagonistic effect of MPV-1743 AIII was demonstrated by s tudying the ability of orally administered MPV-1743 AIII to reverse an d prevent the alpha(2)-adrenoceptor agonist detomidine-induced mydrias is in rat. The anti-obesity effect of MPV-1743 AIII was investigated i n genetically obese (fa/fa) Zucker rats in two different phases of obe sity. Chronic treatment with MPV-1743 AIII (0.3-3 mg/kg per day p.o. f or 3 weeks) dose dependently decreased weight gain in early-phase obes ity. In fully established obesity, GDP binding to mitochondria and exp ression of uncoupling protein mRNA were increased in brown adipose tis sue by MPV-1743 AIII indicating an activation of non-shivering thermog enesis. The present study shows that MPV-1743 A III has a modest anti- obesity effect in the genetic rodent model of obesity. The relative im portance of alpha(2)- and alpha(1)-adrenoceptors and imidazoline I-2b- binding sites in mediating the effects of MPV-1743 AIII needs further evaluation. (C) 1997 Elsevier Science B.V.