Characterization of the V1a antagonist, JNJ-17308616, in rodent models of anxiety-like behavior
Characterization of the V1a antagonist, JNJ-17308616, in rodent models of anxiety-like behavior
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DOI：
10.1007/s00213-008-1354-x
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发表时间：
2009-03-01
影响因子：
3.4
通讯作者：
Hodgson, R. A.
中科院分区：
文献类型：
--
作者：
Bleickardt, C. J.;Mullins, D. E.;Hodgson, R. A.
加压素（AVP）在调节焦虑中起作用，这被认为是部分通过V1 a受体介导的。最近，JNJ-17308616被确定为V1 a拮抗剂。这项工作的目的是评估JNJ-17308616的V1 a受体亲和力和选择性以及在焦虑样行为动物模型中的体内疗效。测定了JNJ-17308616对人和大鼠V1 a、V1 b、V2和催产素受体的亲和力。AVP的中枢给药诱导通过V1 a受体介导的抓挠反应。使用对抓挠的抑制作为体内效力的行为测量。在5种焦虑模型中检测了JNJ-17308616：大鼠高架十字迷宫（EZM）、大鼠高架零迷宫（EZM）、大鼠条件性舔抑制（CLS）、大鼠幼仔分离诱导的超声发声（USV）和小鼠大理石掩埋（MMB）。证实了JNJ-17308616与人V1 a受体的高亲和力（K（i）5.0 nM）。然而，大鼠V1 a受体亲和力更适中（K（i）216 nM），并且该化合物对大鼠V2受体没有选择性（K（i）276 nM）。在100 mg/kg剂量下，JNJ-17308616显著降低了EZM、USV和MMB的焦虑样行为;在30 mg/kg剂量下，JNJ-17308616对EZM和CLS有效。JNJ-17308616既不损害社会识别，也不降低自主活动。这些结果表明V1 a受体拮抗剂作为新型抗焦虑药的潜力。需要具有比JNJ-17308616更高V1 a受体选择性的工具化合物来得出关于V1 a受体在情感障碍中作用的精确结论。
Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially mediated through the V1a receptor. Recently, JNJ-17308616 was identified as a V1a antagonist.The purpose of this work was to assess V1a receptor affinity and selectivity of JNJ-17308616 and in vivo efficacy in animal models of anxiety-like behavior.The affinity of JNJ-17308616 for the human and rat V1a, V1b, V2, and oxytocin receptors was determined. Central administration of AVP induces a scratching response mediated through the V1a receptor. Inhibition of scratching was used as a behavioral measure of in vivo potency. JNJ-17308616 was tested in five models of anxiety: rat elevated plus-maze (EPM), rat-elevated zero-maze (EZM), rat-conditioned lick suppression (CLS), rat pup separation-induced ultrasonic vocalizations (USV), and mouse marble burying (MMB).High affinity for the human V1a receptor (K (i) 5.0 nM) was confirmed. However, the rat V1a receptor affinity was more modest (K (i) 216 nM), and the compound was not selective over the rat V2 receptor (K (i) 276 nM). At 100 mg/kg, JNJ-17308616 significantly reduced anxiety-like behavior in EPM, USV, and MMB; at 30 mg/kg, it was effective in EZM and CLS. JNJ-17308616 neither impaired social recognition nor reduced locomotor activity.These results demonstrate the potential for V1a receptor antagonists as novel anxiolytics. Tool compounds that have greater V1a receptor selectivity than JNJ-17308616 are necessary to make precise conclusions about the role of the V1a receptor in affective disorders.