Preclinical evaluation of intravenous NAX 810‐2, a novel GalR2‐preferring analog, for anticonvulsant efficacy and pharmacokinetics

Summary Objective Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810‐2, a galanin receptor subtype 2 (GalR2)‐preferring galanin analog, possesses 15‐fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810‐2 in mice. Methods NAX 810‐2 was administered by intravenous (i.v.; tail vein, bolus) injection to fully kindled (corneal kindling assay) or naive CF‐1 mice (6 Hz assay and pharmacokinetic studies). Plasma NAX 810‐2 levels were determined from trunk blood samples. NAX 810‐2 was also added to human plasma at various concentrations for determination of plasma protein binding. Results In the mouse corneal kindling model, NAX 810‐2 dose‐dependently blocked seizures following intravenous administration (median effective dose [ED50], 0.5 mg/kg). In the mouse 6 Hz (32 mA) seizure model, it was demonstrated that NAX 810‐2 dose‐dependently blocked seizures following bolus administration (0.375–1.5 mg/kg, i.v.; ED50, 0.7 mg/kg), with a time‐to‐peak effect of 0.5 h posttreatment. Motor impairment was observed at 1.5 mg/kg, i.v., whereas one‐half of this dose, 0.75 mg/kg, i.v., was maximally effective in the 6 Hz test. Plasma levels of NAX 810‐2 show linear pharmacokinetics following intravenous administration and a half‐life of 1.2 h. Functional agonist activity studies demonstrate that NAX 810‐2 effectively activates GalR2 at therapeutic concentrations. Significance These studies further suggest the potential utility of NAX 810‐2 as a novel therapy for epilepsy.