Co 102862

V102862 (Co 102862): a potent, broad-spectrum state-dependent blocker of mammalian voltage-gated sodium channels.[Pubmed:15778702]

Br J Pharmacol. 2005 Mar;144(6):801-12.

1. 4-(4-Fluorophenoxy)benzaldehyde semicarbazone (V102862) was initially described as an orally active anticonvulsant with robust activity in a variety of rodent models of epilepsy. The mechanism of action was not known. We used whole-cell patch-clamp techniques to study the effects of V102862 on native and recombinant mammalian voltage-gated Na+ channels. 2. V102862 blocked Na+ currents (I(Na)) in acutely dissociated cultured rat hippocampal neurons. Potency increased with membrane depolarization, suggesting a state-dependent mechanism of inhibition. There was no significant effect on the voltage dependence of activation of I(Na). 3. The dissociation constant for the inactivated state (K(I)) was approximately 0.6 microM, whereas the dissociation constant for the resting state (K(R)) was >15 microM. 4. The binding to inactivated channels was slow, requiring a few seconds to reach steady state at -80 mV. 5. The mechanism of inhibition was characterized in more detail using human embryonic kidney-293 cells stably expressing rat brain type IIA Na+ (rNa(v)1.2) channels, a major Na+ channel alpha subunit in rat hippocampal neurons. Similar to hippocampal neurons, V102862 was a potent state-dependent blocker of rNa(v)1.2 channels with a K(I) of approximately 0.4 microM and K(R) approximately 30 microM. V102862 binding to inactivated channels was relatively slow (k(+) approximately = 1.7 microM(-1) s(-1)). V102862 shifted the steady-state availability curve in the hyperpolarizing direction and significantly retarded recovery of Na+ channels from inactivation. 6. These results suggest that inhibition of voltage-gated Na+ channels is a major mechanism underlying the anticonvulsant properties of V102862. Moreover, understanding the biophysics of the interaction may prove to be useful in designing a new generation of potent Na+ channel blocker therapeutics.

Development of a high-performance liquid chromatographic-tandem mass spectrometric method for the determination of pharmacokinetics of Co 102862 in mouse, rat, monkey and dog plasma.[Pubmed:11129068]

J Chromatogr B Biomed Sci Appl. 2000 Nov 10;749(1):1-15.

A method for determining concentration levels of Co 102862 in mouse, rat, monkey and dog plasma was validated in the range of 5 to 2000 ng/ml using 200 microl plasma sample volume. This validation report describes the linearity, specificity, sensitivity, reproducibility, accuracy, recovery and stability of the analytical method. The inter-day RSD ranged from 3.5 to 10.1%, intra-day RSD from 0.6 to 5.7% and intra-day accuracy (mean absolute percent difference) ranged from 2.2 to 14.9% for rat, monkey and dog plasma. A mini-validation (5-2000 ng/ml) of Co 102862 was performed in mouse plasma using the same methods. Additionally, the assay range at the low end was successfully extended to 0.5 ng/ml for monkey plasma. The method was used for the routine analysis of Co 102862 in mouse, rat, monkey and dog plasma and summary of the pharmacokinetic data are presented.

Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide: a potent, broad-spectrum state-dependent sodium channel blocker for treating pain states.[Pubmed:16728593]

J Pharmacol Exp Ther. 2006 Sep;318(3):1083-93.

Voltage-gated Na(+) channels may play important roles in establishing pathological neuronal hyperexcitability associated with chronic pain in humans. Na(+) channel blockers, such as carbamazepine (CBZ) and lamotrigine (LTG), are efficacious in treating neuropathic pain; however, their therapeutic utility is compromised by central nervous system side effects. We reasoned that it may be possible to gain superior control over pain states and, in particular, a better therapeutic index, by designing broad-spectrum Na(+) channel blockers with higher potency, faster onset kinetics, and greater levels of state dependence than existing drugs. 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA) is a novel structural analog of the state-dependent Na(+) channel blocker V102862 [4-(4-fluorophenoxy)benzaldehyde semicarbazone]. Tested on recombinant rat Na(v)1.2 channels and native Na(+) currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000 times more potent, had 2000-fold faster binding kinetics, and > or =10-fold higher levels of state dependence than CBZ and LTG. Tested in rat pain models against mechanical endpoints, PPPA had minimal effective doses of 1 to 3 mg/kg p.o. in partial sciatic nerve ligation, Freund's complete adjuvant, and postincisional pain. In all cases, efficacy was similar to clinically relevant comparators. Importantly, PPPA did not produce motor deficits in the accelerating Rotarod assay of ataxia at doses up to 30 mg/kg p.o., indicating a therapeutic index >10, which was superior to CBZ and LTG. Our experiments suggest that high-potency, broad-spectrum, state-dependent Na(+) channel blockers will have clinical utility for treating neuropathic, inflammatory, and postsurgical pain. Optimizing the biophysical parameters of broad-spectrum voltage-gated Na(+) channel blockers may lead to improved pain therapeutics.