Migraine, a recurring type of headache is caused by a hyperactivity of the trigeminovascular system (TGVS), where the trigeminal ganglia (TG) play an important role. This hyperactivity might originate from a deficit in the GABAergic inhibitory system in the TG. Examination of recent reports indicate that α6β2/3γ2 GABA<sub>A</sub>R selective ligands may be important for the treatment of trigeminal orofacial pain and neuropsychiatric disorders with sensory-motor gating deficits. A mouse model of migraine was adapted to investigate the possibility of the origin of hyperactivity from the GABAergic system in TG. Migraine-like facial pain scores were measured using the mouse grimace scale. The α6GABAAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both migraine abortive and prophylactic effects in repeated NTG-treated mice, comparable with clinically used anti-migraine agents, sumatriptan and topiramate, respectively. DK-1-56-1 was also active in models of trigeminal orofacial pain and in a model of Tourette's syndrome. Emphasis here is on the antimigraine activity.

Development of α<sub>6</sub>GABAA receptor positive allosteric modulators to treat migraine via compensating GABAergic deficits in trigeminal ganglia

ACS Spring 2022

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Development of α6GABAA receptor positive allosteric modulators to treat migraine via compensating GABAergic deficits in trigeminal ganglia

Development of α₆GABAA receptor positive allosteric modulators to treat migraine via compensating GABAergic deficits in trigeminal ganglia