4-P-PDOT is an orally active, highly selective melatonin MT2 receptor antagonist. 4-P-PDOT selectivity for the MT2 receptor is over 300 times greater than for MT1 (Ki values of 0.46nM and 56nM, respectively)[1-2]. 4-P-PDOT is primarily used in the field of neuroscience, particularly for research on sleep, circadian rhythms, and related cognitive functions[3-4].
In vitro, 4-P-PDOT (10μM) pretreatment of H9c2 cardiomyocytes for 4 hours, followed by anoxia/reoxygenation (A/R) injury, 4-P-PDOT significantly attenuated melatonin's protective effect on cell viability. 4-P-PDOT also exacerbated cell apoptosis, oxidative stress, and mitochondrial dysfunction[5]. 4-P-PDOT (10μM) was used to treat bone marrow mesenchymal stem cells from ovariectomized rats (after 2 hours of exposure to 100μM H₂O₂, treated for 72 hours). 4-P-PDOT significantly abolished melatonin's protective effect against oxidative stress-induced cellular senescence[6].
In vivo, 4-P-PDOT (5μg/μL; 1μL) was microinjected into the olfactory bulb of 6-OHDA Parkinson's disease model rats (single injection 7 days after injury). In the 6-OHDA-injured rats, 4-P-PDOT significantly induced antidepressant-like behaviors (reducing immobility time and increasing swimming time in the forced swim test)[7]. In a PTSD-like mouse model induced by 5 consecutive days of foot shock, 4-P-PDOT (2mM; 0.1mL/day) was intraperitoneally injected 15 minutes before melatonin (2mM) administration for two weeks. 4-P-PDOT slightly blocked melatonin's improvement of PTSD-like behaviors and mildly attenuated melatonin's restorative effects on serum GABA and cortisol levels[8].
References:
[1] Dubocovich ML. Melatonin receptors: are there multiple subtypes? Trends Pharmacol Sci. 1995 Feb;16(2):50-6.
[2] Shin EJ, Chung YH, Le HL, et al. Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential. Int J Neuropsychopharmacol. 2014 Dec 30;18(6):pyu105.
[3] Dubocovich ML, Masana MI, Iacob S, et al. Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn Schmiedebergs Arch Pharmacol. 1997 Mar;355(3):365-75.
[4] Shin EJ, Chung YH, Le HL, et al. Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential. Int J Neuropsychopharmacol. 2014 Dec 30;18(6):pyu105.
[5] Wu J, Yang Y, Gao Y, et al. Melatonin Attenuates Anoxia/Reoxygenation Injury by Inhibiting Excessive Mitophagy Through the MT2/SIRT3/FoxO3a Signaling Pathway in H9c2 Cells. Drug Des Devel Ther. 2020 May 25;14:2047-2060.
[6] Chen W, Lv N, Liu H, et al. Melatonin Improves the Resistance of Oxidative Stress-Induced Cellular Senescence in Osteoporotic Bone Marrow Mesenchymal Stem Cells. Oxid Med Cell Longev. 2022 Jan 18;2022:7420726.
[7] Noseda ACD, Rodrigues LS, Targa ADS, et al. MT2 melatonin receptors expressed in the olfactory bulb modulate depressive-like behavior and olfaction in the 6-OHDA model of Parkinson's disease. Eur J Pharmacol. 2021 Jan 15;891:173722.
[8] Xu Z, Li W, Sun Y, et al. Melatonin alleviates PTSD-like behaviors and restores serum GABA and cortisol levels in mice. Psychopharmacology (Berl). 2023 Feb;240(2):259-269.
4-P-PDOT是一种具有口服活性的、高选择性的褪黑激素MT2受体拮抗剂，它对MT2受体的选择性是MT1的300倍以上（Ki值分别为0.46nM和56nM）[1-2]。4-P-PDOT主要用于神经科学领域，特别是睡眠、 circadian 节律及相关认知功能的研究[3-4]。
在体外，4-P-PDOT（10μM）预处理H9c2心肌细胞4小时，随后进行缺氧/复氧（A/R）损伤，4-P-PDOT显著减弱了褪黑素对细胞存活率的提升作用，并加剧了细胞凋亡、氧化应激和线粒体功能障碍[5]。4-P-PDOT（10μM）体外处理卵巢切除大鼠骨髓间充质干细胞（在100μM H₂O₂暴露2小时后处理72小时），4-P-PDOT显著消除了melatonin对氧化应激诱导的细胞衰老的保护作用[6]。
在体内，4-P-PDOT（5μg/μL；1μL）微注射到嗅球处理6-OHDA帕金森病模型大鼠（在损伤后7天单次注射），4-P-PDOT在6-OHDA损伤大鼠中显著诱导抗抑郁样行为（减少强迫游泳测试中的不动时间，增加游泳时间）[7]。4-P-PDOT（2mM；0.1mL/day）在褪黑素（2mM）注射前15分钟腹腔注射处理创伤后应激障碍样小鼠（连续5天足底电击诱导）两周，4-P-PDOT轻微阻断了褪黑素对PTSD样行为的改善作用，并轻微减弱了褪黑素对血清GABA和皮质醇水平的恢复作用[8]。