title: Pharmacological effects of ATI22-107 [2-(2-{2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester)], a novel dual pharmacophore, on myocyte calcium cycling and contractility.
abstract: Historically, inhibitors of type III phosphodiesterases (PDE-III) have been effective inotropes in mammalian myocardium, but their clinical utility has been limited by adverse events, including arrhythmias that are considered to be due to Ca(2+) overload. ATI22-107 [2-(2-{2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester)], a novel, dual pharmacophore compound, was designed to simultaneously inhibit the cardiac phosphodiesterase (PDE-III) and produce inotropic effects, whereas inhibiting the L-type calcium channel (LTCC) was designed to minimize increases in diastolic Ca(2+). We compared the effects of ATI22-107 and enoximone, a pure PDE-III inhibitor, on the Fluo-3 calcium transient in normal feline ventricular myocytes and trabeculae. Enoximone-induced dose-dependent increases in peak [Ca(2+)](i), diastolic [Ca(2+)](i), T50, and T75. ATI22-107 demonstrated similar dose-dependent increases in peak [Ca(2+)](i) at 300 nM and 1.0 microM doses, with no further increases at higher doses. Throughout the dosing range, ATI22-107 induced much smaller, if any, increases in diastolic [Ca(2+)](i), T(25), and T(75). Current measurement of LTCC via patch-clamp techniques revealed dose-dependent decreases in LTCC current with an increasing dose of ATI22-107, thereby validating the dual functionality of the drug that has been proposed in this study. Studies in isolated trabeculae demonstrated that enoximone-induced a dose-dependent augmentation of the entire force-frequency relation in normal myocardium, whereas augmentation of contractility was only observed at lower stimulation frequencies with ATI22-107. These results demonstrate the effects of the LTCC-antagonizing moiety of ATI22-107 and suggest that the novel simultaneous combination of PDE-III and LTCC inhibition by one molecule may produce a favorable profile of limited inotropy without detrimental effects of increased diastolic [Ca(2+)](i).
authors.affiliation: Department of Physiology, Temple University School of Medicine, 3420 N. Broad Street, Room 805 MRB, Philadelphia, PA 19140, USA.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Jung
authors.forename: Michael P
authors.initials: MP
authors.lastname: Quaile
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Mills
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bednarik
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000814:Aniline Compounds; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D002469:Cell Separation; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004305:Dose-Response Relationship, Drug; D017335:Enoximone / Q000494:pharmacology; D005456:Fluorescent Dyes; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D014966:Xanthenes
chemical_list: C497719:2-(2-(2-(2-chloro-4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)acetylamino)ethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester; D000814:Aniline Compounds; D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D005456:Fluorescent Dyes; D010726:Phosphodiesterase Inhibitors; D014966:Xanthenes; C059715:Fluo-3; D017335:Enoximone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D009543:Nifedipine; D002118:Calcium