TAK-041 is a first-in-class, potent, and selective small-molecule G protein-coupled receptor 139 (GPR139) agonist with an EC50 of 22 nM that is being developed for treating cognitive impairment and negative symptoms associated with schizophrenia. GPR139 is almost exclusively expressed in the central nervous system, and the highest expression of GPR139 receptors has been reported in the habenula[1], a brain region that has been shown to be critically involved in addiction, anxiety, and mood regulation[2,3] The role of orphan G protein-coupled receptors, including GPR139, in the pathophysiology of different diseases and disorders including anxiety, depression, schizophrenia, epilepsy, Alzheimer disease, Parkinson disease, and substance abuse disorders was recently discussed[4].
TAK-041 can block the suppression in neuronal firing brought about by MOR agonists [5]. The systems level, the interaction is indicated by the ability of MOR antagonists to counteract some of the behavioral impacts of GPR139 knockout[6].TAK-041 might suppress MOR activity. This is unlikely to contribute to the observed pro-motivational effects of TAK-041, though, because MOR knockout and antagonism decreased conditioned responding for food rewards[7-10].
TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived. This effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress.
Tak-041 may be useful in the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction . Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). Findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11]. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia.
References:
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[3].Batalla A, Homberg J R, Lipina T V, et al. The role of the habenula in the transition from reward to misery in substance use and mood disorders[J]. Neuroscience & Biobehavioral Reviews, 2017, 80: 276-285.
[4].Alavi M S, Shamsizadeh A, Azhdari-Zarmehri H, et al. Orphan G protein-coupled receptors: The role in CNS disorders[J]. Biomedicine & Pharmacotherapy, 2018, 98: 222-232.
[5].Stoveken H M, Zucca S, Masuho I, et al. The orphan receptor GPR139 signals via Gq/11 to oppose opioid effects[J]. Journal of Biological Chemistry, 2020, 295(31): 10822-10830.
[6].Dao M, Stoveken H M, Cao Y, et al. The role of orphan receptor GPR139 in neuropsychiatric behavior[J]. Neuropsychopharmacology, 2022, 47(4): 902-913.
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[10]Carlson H N, Murphy C, Pratt W E. Shifting motivational states: The effects of nucleus accumbens dopamine and opioid receptor activation on a modified effort-based choice task[J]. Behavioural Brain Research, 2021, 399: 112999.
[11]. Rabiner E A, Uz T, Mansur A, et al. Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C] PHNO PET[J]. Neuropsychopharmacology, 2022, 47(7): 1405-1412.
[12]. Yin W, Han D, Khudyakov P, et al. A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK‐041 in healthy participants and patients with stable schizophrenia[J]. British Journal of Clinical Pharmacology, 2022.
TAK-041 是一流的、有效的、选择性的小分子 G 蛋白偶联受体 139 (GPR139) 激动剂，EC50 为 22 nM，正在开发用于治疗与精神分裂症相关的认知障碍和阴性症状。 GPR139 几乎只在中枢神经系统中表达，据报道，在缰核[1] 中 GPR139 受体的表达最高，该大脑区域已被证明与成瘾、焦虑症密切相关和情绪调节[2,3] 孤儿 G 蛋白偶联受体（包括 GPR139）在不同疾病和障碍（包括焦虑症、抑郁症、精神分裂症、癫痫、阿尔茨海默病、帕金森病）的病理生理学中的作用最近讨论了疾病和药物滥用障碍[4]。
TAK-041 可以阻断 MOR 激动剂对神经元放电的抑制[5]。在系统层面，相互作用由 MOR 拮抗剂抵消 GPR139 敲除的一些行为影响的能力表明[6]。TAK-041 可能抑制 MOR 活性。不过，这不太可能有助于观察到 TAK-041 的促动机作用，因为 MOR 敲除和拮抗作用降低了对食物奖励的条件反应[7-10]。
TAK-041 增加了仅极少食物剥夺的小鼠获得甜味味觉奖赏的努力。 TAK-041 的这种作用在对照小鼠和由慢性社会压力诱导的努力反应不足的小鼠中均有发生。
Tak-041 可用于治疗精神分裂症和其他与社交和认知功能障碍相关的疾病。用 TAK-041 预处理显着减弱了先验定义区域（壳核和腹侧纹状体:分别为 26% 和 18%）中 d-苯丙胺诱导的 BPND 减少。研究结果表明，TAK-041 进入人脑并与 GPR139 相互作用以影响内源性多巴胺释放。 [11]. TAK-041 具有近乎线性的药代动力学特征，在所有测试剂量中具有快速吸收和 170-302 小时的长半衰期。精神分裂症患者的全身暴露量比健康志愿者低 22-30%。 TAK-041 在健康志愿者和患有精神分裂症的成年人中普遍耐受良好。