The structurally and evolutionarily closely related neuropeptides vasopressin and oxytocin are known to play an important role in the regulation of social behavior in animals and humans. Intranasal administration of vasopressin was shown to modulate the social brain, increasing threat perception in healthy volunteers and impairing emotion recognition in men. Furthermore, elevated vasopressin levels in plasma as well as genetic variation in the vasopressin receptor 1a gene (AVPR1A) have been associated with autism. Altogether, this suggests that a vasopressin 1a (V1a) receptor antagonist has the potential to treat disorders with social emotional dysfunction, including autism spectrum disorder (ASD).<br/>Currently no treatments are available for the ASD core social communication deficits. Evaluation of V1a receptor blockade in animal models with the potential for translational validity has so far been hampered by the lack of selective and robustly brain penetrant small molecule antagonists. In a move towards the validation of V1a receptor antagonism for the treatment of social communication deficits of autism directly in humans we had conducted a proof-of-mechanism study with RG7713, a tool compound which has a PK-PD profile suitable for humans but not rodents. Here we report the discovery of RG7314, the first V1a receptor antagonist developed for the treatment of social communication deficits in ASD. While a phase 2 study in adults has already been completed, evaluation in children and adolescents is ongoing.

Discovery of RG7314: A vasopressin 1a receptor antagonist for the treatment of social communication deficits in autism spectrum disorders

254th National Meeting (2017)

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