LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

Marie-Céline Frantz (1) , Lucie P. Pellissier (2) , Elsa Pflimlin (1) , Stéphanie Loison (1) , Jorge Gandía (2) , Claire Marsol (1, 3, 4) , Thierry Durroux (5) , Bernard Mouillac (5) , Jérôme Becker (2) , Julie Le Merrer (2) , Christel Valencia (3, 4) , Pascal Villa (3, 4) , Dominique Bonnet (1, 3) , Marcel Hibert (1, 3)

1 LIT - Laboratoire d'Innovation Thérapeutique
2 PRC - Physiologie de la reproduction et des comportements [Nouzilly]
3 Centre de recherche du médicament Medalis - Drug Discovery Center [LabEx]
4 PCBiS - Plate-forme de chimie biologique intégrative de Strasbourg
5 IGF - Institut de Génomique Fonctionnelle

Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V-1a and V-2 vasopressin receptor subtypes (V-1a-R and V-2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure affinity and structure efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.

Mots clés: randomized controlled-trial; spectrum disorder; intranasal oxytocin; human vasopressin; united-states; mice lacking; in-vivo; antagonist; behavior

Mots clés: mu-opioid-receptor

Domaines: Chimie; Chimie thérapeutique

Marie-Céline Frantz, Lucie P. Pellissier, Elsa Pflimlin, Stéphanie Loison, Jorge Gandía, et al.. LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism. Journal of Medicinal Chemistry, 2018, 61 (19), pp.8670-8692. ⟨10.1021/acs.jmedchem.8b00697⟩. ⟨hal-02366272⟩