SAN711, a Subtype Selective Positive Allosteric Modulator of GABA A α3 Receptors as a Novel Treatment for Trigeminal Neuralgia

Objective To investigate the effect of SAN711, a selective GABA A α3 receptor positive allosteric modulator, on electrocutaneous stimulation‐induced facial pain in rats. Hypothesis Trigeminal neuralgia is a disorder of the trigeminal sensory system, described as an excruciating, sporadic, and sudden burning facial pain lasting from seconds to minutes per episode. Standard of care treatment consists of voltage‐gated sodium channel blockers (ie. carbamazepine and oxcarbazepine) and off‐label use of drugs that also target the GABAergic system (eg. sodium valproate, lamotrigine). These treatments are non‐selective, resulting in dose limiting tolerability issues. In the present study, we examined the effect of SAN711, a selective GABA A α3 receptor positive allosteric modulator, in a rat model of orofacial pain involving activation of the trigeminal sensory system. Methods The left depilated cheek of Sprague‐Dawley rats was electrocutaneously stimulated for 1 h at 0.4 mA intensity, 10 ms duration, and 1 s inter‐pulse intervals. Facial withdrawal was measured after 22 h of electrocutaneous stimulation following application of Von Frey filaments for mechanical allodynia and a heat lamp (hot) and acetone test (cold) for thermal allodynia. SAN711 was administered acutely (1, 3, 10 mg/kg, po) after electrocutaneous stimulation and prophylactically (0.3, 1, 3 mg/kg, po, QD) for 7 days prior to electrocutaneous stimulation. Carbamazepine (30 mg/kg, po), the first line treatment for trigeminal neuralgia, was used as a reference standard. Results All rats developed electrocutaneously stimulated mechanical and thermal allodynia. Carbamazepine significantly reversed mechanical and thermal allodynia. Acute treatment with SAN711 significantly and dose‐dependently reversed mechanical (Figure 1) and thermal (hot and cold) allodynia with a minimum effective dose between 1‐3 mg/kg. The highest acute dose of SAN711 (10mg/kg) showed an effect size similar to that of carbamazepine. Prophylactic treatment with SAN711 significantly and dose‐dependently prevented development of electrocutaneously stimulated sensitization and lowered the minimally effective dose to 0.3‐1 mg/kg (Figure 2). Conclusions There have been no new drugs approved for trigeminal neuralgia in over 50 years. Development of safe and effective pharmacological treatments for this debilitating disease are urgently needed. Our data provide support for the development of SAN711 as a novel treatment for trigeminal neuralgia. First‐in‐human clinical trials are now being planned.