Potassium channel modulator at ECTRIMS

A board to discuss future MS therapies in early stage (Phase I or II) trials.

Potassium channel modulator at ECTRIMS

Postby dignan » Sat Oct 13, 2007 9:20 am

I include this preclinical abstract because the substance being tested is a voltage-gated potassium channel modulator. I think this strategy could be promising to provide neuroprotection, and this is the first oral drug I've seen in the preclinical stage that goes after Kv1.3 (1.3 is the channel of interest for MS).

BNC-245 – a novel compound for multiple sclerosis treatment

E. Andriambeloson, S. Wagner, L. Gorj, J. Bindler, J. Mould, B. Flynn (Illkirch, F; Adelaide, AUS)

The Kv1.3 ion channel modulates the function of autoreactive effector memory T-cells (TEM) which have been implicated in the pathogenesis of autoimmune diseases such multiple sclerosis (MS) and rheumatoid arthritis.

Under whole cell patch clamp conditions, BNC-245 exhibits 5 fold selectivity for Kv1.3 over Kv1.1 or Kv1.5 channels with an IC50 of 75 nM. Consistent with the role of Kv1.3 in T cell activation, BNC-245 reduces the proliferation of MBP- activated memory T cells in a dose dependent manner. Pharmacokinetic studies indicate that BNC-245 has good drug like properties with an oral bioavailability of 90% and a half life of 5 hr.
In the present study, we demonstrate in-vivo efficacy of BNC-245, a novel Kv1.3 channel blocker, in ovalbumin -induced delayed type hypersensitivity (DTH) and myelin basic protein (MBP) –induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats.
BNC-245 administered PO as a single dose on the day of albumin challenge, significantly reduced the DTH response in rats in a dose-dependent manner with a minimum effective dose <= 0.1 mg/kg. In EAE-rats, BNC-245 (30 mg/kg/d) administered from days 8 to 12 post-MBP significantly reduced the severity of the disease (area under curve reduced to 56% of control).

Together, these results indicate that BNC-245 modulates TEM function and attenuates neurological deficits in a rat model of MS, most probably via inhibition of Kv1.3 K+ channels. BNC-245 could therefore provide a novel for treatment for MS and other autoimmune diseases.

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Progesterone and Kv1.3 Potassium Channel

Postby Shayk » Wed Oct 17, 2007 7:41 pm


I think this strategy could be promising to provide neuroprotection, and this is the first oral drug I've seen in the preclinical stage that goes after Kv1.3 (1.3 is the channel of interest for MS).

I agree with you about the potential for neuroprotection and since I'm on a progesterone roll let's not forget that it also impacts the Kv1.3 potassium channel.

A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes
Progesterone effectively blocked a broad spectrum of K+ channels, reducing both Kv1.3 and charybdotoxin-resistant components of KV current and KCa current in T cells, as well as blocking several cloned KV channels expressed in cell lines.

It's available orally (compounded) and in a cream too.

Thanks for posting the abstract and info. It's nice to know they're pursuing the potassium channel angle. In the interim, I'm sticking with progesterone.

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Fight fire with fire

Postby gibbledygook » Fri Jul 11, 2008 6:06 am

1: J Pharmacol Exp Ther. 2001 Oct;299(1):238-46. Links
Capsaicin inhibits Jurkat T-cell activation by blocking calcium entry current I(CRAC).Fischer BS, Qin D, Kim K, McDonald TV.
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Capacitative calcium entry (CCE) through stores-operated Ca2+ channels is an absolute requirement for normal activation of T lymphocytes. Organic blockers/inhibitors of the channel(s) that carry the inward Ca2+ current (I(CRAC)) responsible for CCE are few. Here we show that capsaicin, the pungent ingredient of hot chili pepper, blocks receptor-stimulated Ca2+ entry in Jurkat T cells. Indo-1 measurements of intracellular calcium show that capsaicin blocks CCE without affecting release of inositol-1,4,5-trisphosphate-sensitive internal Ca2+ stores with an IC50 of 32 microM. Block of Ca2+ entry by capsaicin is identical whether CCE is evoked by T-cell receptor (TCR) stimulation, heterologous muscarinic M1 receptor stimulation, or via thapsigargin depletion of internal Ca2+ stores. Patch-clamp experiments show that capsaicin rapidly and reversibly blocks I(CRAC) with an identical dose response as seen with indo-1 measurements. The major voltage-gated K+ channel in Jurkat cells, Kv1.3, is also blocked by capsaicin. Although Kv1.3 block may contribute to reducing CCE by changes in membrane potential, block of I(CRAC) is the primary mechanism by which capsaicin reduces CCE. Capsaicin analogs capsazepine and resiniferatoxin also produce inhibition of CCE via block of I(CRAC). Upon application of capsaicin to Jurkat cells in culture we observed an inhibition of interleukin-2 (IL-2) production in response to TCR stimulation. The dose dependence of capsaicin's reduction of IL-2 was comparable with its block of I(CRAC), thereby illustrating the functional relevance of capsaicin's block of lymphocyte CCE. Thus, capsaicin and its numerous analogs may have potential use as immunomodulatory drugs and should be further investigated in models of inflammation and T-cell activation.
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