TAK-041 是一种有效的选择性 GPR139 激动剂，EC50 为 22 nM。
货号:ajcx12080
CAS:1929519-13-0
分子式:C??H??F?N?O?
分子量：392.33
溶解度:N/A
纯度：98%
存储：Store at -20°C
库存：现货

Background:

TAK-041 is a first-in-class, potent, and selective small-molecule G protein-coupled receptor 139 (GPR139) agonist with an EC₅₀of 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.

参考文献:
[1].HITCHOCK S, Lam B, Monenschein H, et al. 4-oxo-3, 4-dihydro-1, 2, 3-benzotriazines as modulators of gpr139[P]. 2016-5-26.
[2].Fowler C D, Kenny P J. Habenular signaling in nicotine reinforcement[J]. Neuropsychopharmacology, 2012, 37(1): 306.
[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.
[7]Mena J D, Selleck R A, Baldo B A. Mu-opioid stimulation in rat prefrontal cortex engages hypothalamic orexin/hypocretin-containing neurons, and reveals dissociable roles of nucleus accumbens and hypothalamus in cortically driven feeding[J]. Journal of Neuroscience, 2013, 33(47): 18540-18552.
[8]Selleck R A, Lake C, Estrada V, et al. Endogenous opioid signaling in the medial prefrontal cortex is required for the expression of hunger-induced impulsive action[J]. Neuropsychopharmacology, 2015, 40(10): 2464-2474.
[9]Zhang M, Balmadrid C, Kelley A E. Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat[J]. Behavioral neuroscience, 2003, 117(2): 202.
[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‐41 in healthy participants and patients with stable schizophrenia[J]. British Journal of Clinical Pharmacology, 2022.

Protocol:

Cell experiment [1]:
Cell lines	rat, dog, monkey, and human HepatoPac cells
Preparation Method	TAK-041 (2.00 mg) was dispensed into a 4-ml glass vial and stored frozen at -20°C until use. DMSO (509.8 µl) was added to the vial to generate a 10 mM stock solution.A 2-µl aliquot of a 10 µM stock solution of TAK-041 in DMSO was added to 998 µl of Krebs-Henseleit buffer (pH 7.4) to prepare a 20 µM working solution for the hepatocyte incubation. The hepatocyte incubations consisted of (final concentrations) 10 µM TAK-041.A 96-well plate was used for this study. The hepatocyte suspension incubations were initiated with the addition of an equal volume of TAK-041 in incubation buffer to hepatocytes in the plate (final cell concentration of 1 × 106 cells per milliliter, 100-µl total well volume).
Reaction Conditions	20 µM 0/2/4/24/48/168/336h
Applications	TAK-041 exhibited very low turnover in suspended cryopreserved hepatocyte suspensions, with no metabolites observed in human hepatocytes. Incubations conducted for up to 14 days in the HepatoPac model resulted in more robust metabolic turnover. The major biotransformation pathways of TAK-041 proceed via hydroxylation on the benzene ring fused to the oxotriazine moiety and subsequent sulfate, glucuronide, and glutathione conjugation reactions. The glutathione conjugate of TAK-041 undergoes further downstream metabolism to produce the cysteine S-conjugate, which then undergoes N-acetylation to mercapturic acid and/or conversion to β-lyase-derived thiol metabolites. The minor biotransformation pathways include novel ring closure and hydrolysis, hydroxylation, oxidative N-dealkylation, and subsequent reduction. The HepatoPac model shows a notable species difference in the rate and in the extent of metabolic pathways of TAK-041, with dogs having the fastest metabolic clearance and humans the slowest.
Animal experiment [2]:
Animal models	C57BL/6 adult male mice
Preparation Method	Mice in the CSS and CON groups were allocated to three dose groups of TAK-041 suspension, namely 0, 1 or 3 mg/kg in 10 mL/kg vehicle p.o., administered at 60 min prior to test onset on each of the 6 test days ( per group). On the day after behavioral testing, mice were injected once more with their study dose and 60 min later, trunk blood was collected for determination of TAK-041 plasma exposur.
Dosage form	0.3, 1, 3 mg/kg po
Applications	TAK-041 does not alter tonic dopamine release in the nucleus accumbens.TAK-041 increases responding for a gustatory reward in minimally food-deprived mice.TAK-041 does not increase responding for reward in moderately food-deprived rats.TAK-041 does not alter food intake.
参考文献: [1]. Kamel A, Bowlin S, Hosea N, et al. In Vitro Metabolism of Slowly Cleared G Protein-Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism[J]. Drug Metabolism and Disposition, 2021, 49(2): 121-132. [2]. MÜnster A, Sommer S, KÚke?ovÁ D, et al. Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions[J]. Neuropharmacology, 2022, 213: 109078..