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J Med Chem. 2018 Oct 11;61(19):8670-8692. doi: 10.1021/acs.jmedchem.8b00697. Epub 2018 Sep 24.

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

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Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie , UMR7200 CNRS/Université de Strasbourg , 74 Route du Rhin , F-67412 Illkirch , France.
Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, IFCE, Inserm , Université François Rabelais de Tours , F-37380 Nouzilly , France.
LabEx MEDALIS , Université de Strasbourg , F-67000 Strasbourg , France.
PCBIS Plateforme de Chimie Biologique Intégrative de Strasbourg, UMS3286 , CNRS/Université de Strasbourg , F-67000 Strasbourg , France.
Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661 , Université de Montpellier (IFR3) , 141 Rue de la Cardonille , F-34094 Montpellier Cedex 5 , France.


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 V1a and V2 vasopressin receptor subtypes (V1a-R and V2-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.

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