NNC 55-0396 dihydrochloride

Description

NNC 55-0396 is a selective inhibitor of T-type calcium channels that blocks Ca_v3.1 in stably expressing HEK293 cells (IC₅₀ = 6.8 μM) with no discernible effect on high voltage-activated (L-type) channels in INS-1 cells up to a concentration of 100 μM. NNC 55-0396 suppresses tremor in two murine models, the GABA_A α₁-null (20 mg/kg) and harmaline-induced (12.5 mg/kg) tremor models, and was better tolerated than mibefradil . In arterial smooth muscle cells, NCC 55-0396 (IC₅₀ = 80 nM) inhibits voltage-dependent K⁺ channels but does not affect their voltage sensitivity. NNC 55-0396 (1-5 μM) also suppresses angiogenesis in vitro by inhibiting hypoxia-inducible factor-1α activity, and it slows tumor growth of flank xenografts of U87MG cells in mice when administered at 20 mg/kg.

Uses

NNC 55-0396 is a calcium channel protein inhibitor.

Definition

ChEBI: NNC 55-0396 dihydrochloride is t-type calcium channel blocker It has a role as a calcium channel blocker.

Biological Activity

Highly selective T-type calcium channel blocker. Displays IC 50 values of 6.8 and > 100 μ M for inhibition of Cav3.1 T-type channels and HVA currents respectively in INS-1 cells.

in vitro

nnc 55-0396 showed no effect against high voltage calcium channels at 100 μm, but inhibited t-type channels in hek293 cells with a potency comparable to that of mibefradil (ic50 6.8 versus 10.1 μm) [1].

in vivo

nnc 55-0396 was better tolerated than mibefradil in the horizontalwire test. to assess for a potential interaction with harmaline in the inverted wire grid test, mice was given nnc 55-0396, followed by harmaline or vehicle. nnc 55-0396 ameliorated harmaline-induced test deficits. in the gabaa α1-null model, nnc 55-0396 at 12.5 mg/kg suppressed harmaline-induced tremor by half by 20–100 min, whereas mibefradil at the same dose did not significantly affect tremor. in contrast to mibefradil, nnc 55-0396 was well tolerated and suppresses tremor, and exerts less cytochrome p450 inhibition [1].

IC 50

6.8 μm for cav3.1 t-type channel

storage

Desiccate at RT

References

[1] quesada a,bui ph,homanics ge,hankinson o,handforth a. comparison of mibefradil and derivative nnc 55-0396 effects on behavior, cytochrome p450 activity, and tremor in mouse models of essential tremor. eur j pharmacol.2011 may 20;659(1):30-6.