Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO₂ inhalation challenge to induce panic symptoms. In the rat CO₂ model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO₂-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO₂-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO₂ exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

起源于前庭和下丘脑外侧区域的食欲素神经元投射到与焦虑和恐慌相关的神经回路，并且对焦虑刺激具有高度反应性。临床前证据表明，食欲素系统，尤其是食欲素-1 受体 (OX1R)，可能与恐慌和焦虑的病理生理有关。因此，选择性 OX1R 拮抗剂可能构成恐慌和焦虑相关疾病的潜在新治疗策略。在这里，我们表征了一种新型选择性 OX1R 拮抗剂 JNJ-61393215，并在体外测定了其对人和大鼠 OX1R 的亲和力和效力。我们还在进行的首次人体单次和多次递增剂量研究中评估了 JNJ-61393215 的安全性、药代动力学和药效学特性。最后，₂吸入激发诱发恐慌症状。在惊恐焦虑的大鼠 CO _{2模型中，JNJ-61393215 在不改变基线运动或自主活动的情况下，表现出 CO 2}诱导的惊恐样行为的剂量依赖性衰减，并且对自发睡眠的影响最小。在 1 期人体研究中，90 mg 的 JNJ-61393215 显着减少 ( P  < 0.02) CO ₂引起的恐惧和焦虑症状，这与使用阿普唑仑获得的症状相当。最常报告的不良事件是嗜睡和头痛，并且所有事件的严重程度都是轻微的。这些结果支持 JNJ-61393215 的安全性、耐受性和抗焦虑作用，并验证 CO ₂暴露作为一种转化的跨物种实验模型来评估新型抗焦虑药物的治疗潜力。