Target Validation Information
Target ID T51115
Target Name Voltage-dependent L-type calcium channel subunit alpha-1C
Target Type
Successful
Drug Potency against Target CGS-27830 Drug Info IC50 = 592 nM
PD-32577 Drug Info IC50 = 2000 nM [525576]
CORYNANTHEINE Drug Info Ki = 1250 nM [533638]
RAUWOLFIA SERPENTINA ROOT Drug Info Ki = 289 nM [533638]
Ibutilide Drug Info IC50 = 20 nM
NILVADIPINE Drug Info IC50 = 1.04 nM [533081]
SNAP-5089 Drug Info Ki = 670 nM [525611]
CV-4093 Drug Info IC50 = 8.68 nM [533081]
NIGULDIPINE Drug Info Ki = 9 nM [533638]
R-56865 Drug Info IC50 = 760 nM [534727]
Action against Disease Model Ibutilide This study examined the ionic mechanism of ibutilide, a class III antiarrhythmic in clinical use, on freshly isolated h uMan atrial cells. Cells had resting potentials of -71.4 +/- 2.4 mV, action potentials with overshoot of 36.8 +/- 1.8 mV, duration of 265 +/- 89 msec at 90% repolarization and slow repolarization (n = 16). Ibutilide, at 10(-7) M, markedly increased action potential duration. Four types of outward currents were detected: Ito, Iso, a delayed rectifier and IK1. Ibutilide had no inhibitory effect on these outward currents at 10(-7) M (n = 28). In K(+)-free solutions and -40 mV holding potential, mean peak inward current at 20 mV was -1478 +/- 103 pA (n = 12). Ibutilide increased this current to -2347 +/- 75 pA at 10(-7) M, with half maximal effect (Kd) of 0.1 to 0.9 nM between -10 and +40 mV (n = 21). At similar concentrations, the drug increased APD, with Kd of 0.7 and 0.23 nM at 70 and 90% repolarization, respectively (n = 8). Ibutilide shifted the mid-point of the steady-state inactivation curve from -21 to -12.2 mV (n = 6), and reduced current decline during repetitive depolarization (n = 5). The drug induced inward current was carried by Na+o through a nifedipine inhibited inward channel because Na+o removal eliminated the effect, and nifedipine abolished the inward current and the drug induced APD prolongation. We propose that a Na+ current through the L-type Ca++ channel mediates ibutilide's potent clinical class III antiarrhythmic action. [538107] Drug Info
Ibutilide In this study, we compared the effects of ibutilide with those of dofetilide on outward current in mouse atrial t uMor myocytes (AT-1 cells), a preparation in which, unlike guinea pig, a typical IKr is the major delayed rectifier and can be readily recorded in isolation from other currents. In AT-1 cells, ibutilide and dofetilide were both potent IKr blockers, with EC50 values of 20 (n = 12) and 12 (n = 8) nmol/L, respectively, at +20 mV. The time and voltage dependence of IKr inhibition by the two compounds were virtually identical. The following characteristics were most consistent with open channel block: (1) block increased with depolarizing pulses; (2) block increased with longer pulses; (3) currents deactivated more slowly in the presence of drug, resulting in a "crossover" typical of open channel block; and (4) with repetitive pulsing after drug wash-in, use-dependent block was observed. [553200] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations In the present study, we used a third generation, time- and tissue-specific conditional knockout model of the L-type Ca2+ channel Cav1.2 (Cav1.2SMAKO mice) to genetically dissect the effects of mibefradil on T- and L-type Ca2+ channels. Myogenic tone and phenylephrine-induced contraction in hindlimb perfusion experiments were sensitive to mibefradil in control mice, whereas the drug showed no effect in Cav1.2-deficient animals. Mean arterial blood pressure in awake, freely moving control mice was reduced by 38+/-2.5 mm Hg at a dose of 1.25 mg/kg bodyweight mibefradil, but not changed in Cav1.2SMAKO mice. These results demonstrate that the effect of the putative T-type Ca2+ channel-selective blocker mibefradil on blood pressure and small vessel myogenic tone is mediated by the Cav1.2 L-type Ca2+ channel.
References
Ref 525576Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers.
Ref 538107Ionic mechanism of ibutilide in human atrium: evidence for a drug-induced Na+ current through a nifedipine inhibited inward channel. J Pharmacol Exp Ther. 1998 Jul;286(1):9-22.
Ref 533638J Med Chem. 1995 Sep 15;38(19):3681-716.Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Ref 533638J Med Chem. 1995 Sep 15;38(19):3681-716.Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Ref 533081J Med Chem. 1989 Oct;32(10):2399-406.Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity.
Ref 525611Bioorg Med Chem Lett. 1999 Oct 4;9(19):2843-8.Design and synthesis of novel dihydropyridine alpha-1a antagonists.
Ref 533081J Med Chem. 1989 Oct;32(10):2399-406.Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity.
Ref 533638J Med Chem. 1995 Sep 15;38(19):3681-716.Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Ref 553200Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation. 1995 Mar 15;91(6):1799-806.
Ref 534727J Med Chem. 1998 Oct 22;41(22):4309-16.Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 1. 2-(3, 5-di-tert-butyl-4-hydroxyphenyl)-3-(aminopropyl)thiazolidinones.

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