title: Anti-obesity effect of MPV-1743 A III, a novel imidazoline derivative, in genetic obesity.
abstract: MPV-1743 A III ((+/-)-4-(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 alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. erisan@utu.fi
authors.forename: E
authors.initials: E
authors.lastname: Savontaus
authors.forename: A
authors.initials: A
authors.lastname: Raasmaja
authors.forename: J
authors.initials: J
authors.lastname: Rouru
authors.forename: M
authors.initials: M
authors.lastname: Koulu
authors.forename: U
authors.initials: U
authors.lastname: Pesonen
authors.forename: R
authors.initials: R
authors.lastname: Virtanen
authors.forename: J M
authors.initials: JM
authors.lastname: Savola
authors.forename: R
authors.initials: R
authors.lastname: Huupponen
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005260:Female; D006153:Guanosine Diphosphate / Q000378:metabolism; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007192:Indenes; D008297:Male; D009184:Mydriatics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D019440:Anti-Obesity Agents; D007093:Imidazoles; D007192:Indenes; C108487:MPV 1743 AIII; D009184:Mydriatics; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D006153:Guanosine Diphosphate; C041255:detomidine