Sipatrigine (BW 619C89) is a Neuroprotective Agent and a Sodium Channel and Calcium Channel Inhibitor

Abstract

Sipatrigine is a substituted pyrimidine derived from lamotrigine. It attenuates glutamate release in vitro and in vivo, probably as a result of sodium and calcium channel inhibition. It consistently reduces cortical infarct volume in rodent models of global, permanent focal, and transient focal ischemia (typically 50-60% reduction with maximum effective doses >20 mg/kg). Striatal protection was found in some studies but not others. The drug was effective also in a rat optic nerve model of white matter ischemia, providing complete neuroprotection at the highest concentration (100 mM) used. In monkeys, CNS penetration by sipatrigine was rapid and the steady state brain/plasma ratio was >40. In humans, low doses (< 2 mg/kg, then 1 mg/kg/8 h) were well tolerated. At higher doses a significant incidence of hallucinations and vomiting was observed. These adverse effects were speculated to be due to interactions with muscarinic receptors and 5-HT 3 (or sigma) receptors, respectively. Cardiovascular side effects appeared not to be a major concern. In electrophysiological studies, sipatrigine inhibited native neuronal sodium and calcium channels (including L, N, and P/Q type) and recombinant type IIA sodium and N and T type calcium channels, all with similar potency (IC 50 in the range 5-16 mM). Inhibitory potency was increased by high action potential firing frequencies and a depolarized resting voltage. These properties may account for its actions in vitro and in animal models but do not exclude possible additional actions in later stages of ischemic damage.

The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential

“…Inward I Ca,L makes a significant contribution to the plateau phase of the AP 21 and it is therefore likely that partial block of I Ca,L by sipatrigine (IC = 50 −6 μmol/L) contributed to the shortening of APD 30 and, thereby, to the AP triangulation observed with higher concentrations of the drug. The IC 50 values for inhibition by sipatrigine of cardiac I Na (approximately 25 μmol/L) and I Ca,L (approximately 6 μmol/L) in the present study are very similar to those reported for native and recombinant neuronal voltage‐gated Na + (10–50 μmol/L) and various subtypes of Ca 2+ current, including L‐, N‐, P/Q‐, R‐ and T‐type currents (7–16 μmol/L) 1,22–29 . Thus, it can be concluded that sipatrigine shows little selectivity between cardiac and neuronal isoforms of Na + channel or between distinct Ca 2+ channel subtypes, further demonstrating its action as a broad‐spectrum cation channel blocker.…”

“…Intriguingly, the corresponding regions in the IIIS6 and IVS6 domains of the cardiac L‐type Ca 2+ channel and the S6 domain of the cardiac I Kr hERG K + channel are also thought to play a role in drug binding, raising the possibility that sipatrigine may bind to similar regions of the channel pore‐forming α‐subunit of different classes of voltage‐gated cation channels 30,31 . Sipatrigine is highly lipid soluble 1 and the slow onset of current blockade by sipatrigine and the partial recovery on wash‐out of the drug observed for each of the currents in this study are consistent with a requirement for the drug to partition within the membrane for channel blockade.…”

“…Sipatrigine (4‐amino‐2‐(4‐methyl‐1‐piperazinyl)‐5‐(2,3,5‐trichlorophenyl)‐pyrimidine; BW 619C89) is a compound that is structurally related to the anti‐epileptic drug lamotrigine (Fig. 1) and is neuroprotective in models of global and transient cortical ischaemia 1 . Some of the actions of sipatrigine on the central nervous system may be as a result of its ability to interact with a range of neurotransmitter receptor types, whereas its key neuroprotective action of inhibiting glutamate release is most likely to result from its ability to inhibit neuronal sodium and a range of calcium channels, including L‐, N‐, P/Q‐ and T‐type channels (for a review, see Hainsworth et al.…”

“…Although much is known about the neuronal effects of sipatrigine, published data on the cardiovascular effects of this agent are sparse. Intravenous administration of sipatrigine has been observed to produce reductions in arterial blood pressure and heart rate in anaesthetized rats, 1,3,4 indicative of a capacity of this compound to exert direct effects on vascular and cardiac tissues. Moreover, intravenous administration of sipatrigine to conscious Cynomolgus monkeys has been associated with bradycardia and prolongation of the QT interval of the electrocardiogram (ECG) 1 .…”

The Cav2.3 voltage-gated calcium channel in epileptogenesis—Shedding new light on an enigmatic channel

“…Besides, structurally related agents, such as sipatrigine or 202W92 also exert inhibitory effects on Ca v 2.3 with IC 50 values of 10 mM (therapeutically relevant brain concentration: 20-100 mM (sipatrigine) and 56 mM (202W92). In addition, both sipatrigine and 202W92 are neuroprotective agents in animal models of ischemia (Caputi et al, 2001;Hainsworth et al, 2000) and interestingly, were shown to exert anticonvulsant effects in genetically epilepsy-prone rats and DBA/2 audiogenic mice (Hainsworth et al, 2003;Reddy et al, 1998).…”