title: Characterization of the beta-adrenoceptor blocking property of diprafenone in rats: stereoselective interaction, subtype specificity, and sensitization.
abstract: Because of their structural relationship to propranolol, propafenone and diprafenone display beta-adrenoceptor blocking activity in addition to their class Ic antiarrhythmic property. As demonstrated in membranes derived from rat ventricle (predominantly beta 1-adrenoceptors) and rat lung tissue (predominantly beta 2-adrenoceptors), the (-)-enantiomer of diprafenone was about four times more potent (Ki 6.6 nmol/L) than the (+)-enantiomer in displacing [125I]iodocyanopindolol (ICYP) binding. The Ki values for the (+)- and (-)-stereoisomer, racemic (+/-)-diprafenone, and 5-hydroxydiprafenone, the main metabolite of diprafenone in humans, were approximately 2.5 times lower in lung than in ventricular membranes, suggesting very low beta 2-selectivity for diprafenone. The regulatory effect of diprafenone on ventricular beta-adrenoceptors was studied in rats in vivo by prolonged i.p. administration of the drug. Density of beta-adrenoceptors was estimated by ICYP saturation binding after 2-day (4 or 20 mg/kg, b.i.d.) and after 7-day treatment (4 mg/kg, b.i.d.), respectively. For control purposes, different groups of animals were treated with propranolol (1.7 mg/kg, b.i.d., i.p.), isoprenaline (0.1 mg/kg/h via subcutaneously implanted osmotic minipumps), and vehicle (0.9% NaCl) only. Whereas propranolol and isoprenaline produced an increase (7-day treatment) and a decrease (2- and 7-day treatment) in beta-adrenoceptors, respectively, diprafenone did not produce any change in beta-adrenoceptor number, irrespective of the dose and duration of treatment used. Furthermore, the combined administration of diprafenone and isoprenaline did not antagonize isoprenaline-induced down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Institute of Pharmacology, University of Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Nanoff
authors.forename: W
authors.initials: W
authors.lastname: Schütz
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020120:Iodocyanopindolol; D008297:Male; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011405:Propafenone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D011943:Receptors, Adrenergic, beta; C047546:diprafenone; D011405:Propafenone; D020120:Iodocyanopindolol; D010869:Pindolol