LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism
LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism
复制标题
DOI：
10.1021/acs.jmedchem.8b00697
复制
发表时间：
2018-10-11
影响因子：
7.3
通讯作者：
Hibert, Marcel
中科院分区：
文献类型：
--
作者：
Frantz, Marie-Celine;Pellissier, Lucie P.;Hibert, Marcel
催产素（OT）及其受体（OT-R）参与自闭症谱系障碍（ASD）的病因学，OT-R是治疗干预的潜在靶点。目前很少有非肽类催产素激动剂的报道。它们的分子和体内药理学仍有待澄清，并且它们中没有一种在与ASD相关的动物模型中显示出有效改善社会互动。为了使中枢活性非肽类完全激动剂的设计合理化，我们以系统的方式研究了V-1a和V-2加压素受体亚型（V-1a-R和V-2-R）和催产素受体的代表性配体的亲和力和功效的结构决定因素。我们的研究结果证实了微妙的结构亲和性和结构功效的关系，加压素/催产素受体配体周围，但导致第一个非肽OT受体激动剂在小鼠模型中的ASD后，外周IP管理。
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.