MLS-1547 is a potent and G protein-biased agonist of the dopamine D2 receptor (D2R), exhibiting an EC50 value of 0.37nM and an Emax of approximately 90% in a D2R-mediated D2-Gqi5 calcium mobilization assay[1]. MLS-1547 effectively stimulates G protein-mediated signaling while fully inhibiting forskolin-stimulated cAMP production, without effectively recruiting β-arrestin[1,2]. MLS-1547 has been widely used in research areas such as D2R functionality, and in elucidating the respective roles of G proteins and β-arrestin in neurophysiology, psychiatric disorders, and drug development[3,4].
In vitro, treatment of the rat PRL-secreting pituitary tumor cell line MMQ with MLS-1547 (100nM) for 72h resulted in only a slight reduction in cell proliferation (-13.2 ± 7.4%), an effect that was completely abolished by pretreatment with 100ng/μL pertussis toxin (PTX). Furthermore, incubation of MMQ cells with MLS-1547 (100nM) for 24h effectively reduced prolactin (PRL) secretion (-34.7 ± 29.5%)[5]. In rat pituitary tumor cell line GH3 treated with MLS-1547 (10μM) for 48h, a more pronounced response was observed, leading to an 83% reduction in cell viability compared to controls. This inhibitory effect on GH3 cell viability could be rescued by co-treatment with haloperidol (10μM) and PTX (100nM)[6].
In vivo, bilateral double infusion of MLS-1547 (5mM; 0.5μL per side) into the medial prefrontal cortex (mPFC) of Sprague-Dawley rats significantly reduced risk-seeking behavior in a cue-guided risky decision-making task (by an average of 14.941% compared to the control group), without impairing cue recognition, supporting its potential role in modulating risk decision-making through the prefrontal dopaminergic system[7].
References:
[1] FREE R B, CHUN L S, MORITZ A E, et al. Discovery and characterization of a G protein-biased agonist that inhibits β-arrestin recruitment to the D2 dopamine receptor[J]. Molecular Pharmacology, 2014, 86(1): 96-105.
[2] CHUN L S, VEKARIYA R H, FREE R B, et al. Structure-activity investigation of a G protein-biased agonist reveals molecular determinants for biased signaling of the D2 dopamine receptor[J]. Frontiers in Synaptic Neuroscience, 2018, 10: 2.
[3] WILLETTE B K A, SOTO M S, GONYE E C, et al. Investigating the interactions of GRK2 with a G-protein signaling-biased D2 dopamine receptor[J]. The FASEB Journal, 2018, 32: 827.13-827.13.
[4] CHEN H, XIONG X X, JIN S Y, et al. Dopamine D2 receptors in pyramidal neurons in the medial prefrontal cortex regulate social behavior[J]. Pharmacological Research, 2024, 199: 107042.
[5] DI MURO G, MANGILI F, ESPOSITO E, et al. A β-arrestin 2-biased dopamine receptor type 2 (DRD2) agonist is more efficacious than cabergoline in reducing cell proliferation in PRL-secreting but not in non-functioning pituitary tumor cells[J]. Cancers, 2023, 15(12): 3218.
[6] TAN Z, LEI Z, YAN Z, et al. Exploiting D2 receptor β-arrestin2‐biased signalling to suppress tumour growth of pituitary adenomas[J]. British Journal of Pharmacology, 2021, 178(17): 3570-3586.
[7] YANG M, FU Q, MA C, et al. Prefrontal dopaminergic regulation of cue-guided risky decision-making performance in rats[J]. Frontiers in Behavioral Neuroscience, 2022, 16: 934834.
MLS-1547是一种高效的，对G蛋白信号通路具有偏好性的D2多巴胺受体（D2R）激动剂，在D2R介导的D2-Gqi5钙动员测试中的EC50值为0.37nM，Emax值为~90%[1]。MLS-1547能够有效地刺激G蛋白介导的信号传导，但完全抑制forskolin刺激的cAMP产生，无法有效募集β-arrestin[1,2]。MLS-1547已广泛用于研究D2R功能性、剖析G蛋白与β-arrestin在神经生理、精神疾病及药物开发中各自作用等领域[3,4]。
在体外，MLS-1547（100nM）与大鼠PRL分泌型垂体瘤细胞系MMQ孵育72h，仅引起了轻微的细胞增殖抑制（-13.2 ± 7.4%），且该效应可被100ng/μL百日咳毒素（PTX）预处理后完全阻断。MLS-1547（100nM）与大鼠PRL分泌型垂体瘤细胞系MMQ孵育24h，能有效减少PRL的分泌（-34.7 ± 29.5%）[5]。MLS-1547（10μM）处理大鼠垂体瘤GH3细胞48h，GH3细胞对MLS-1547的响应较为强烈，使得细胞活力较对照降低83%，但MLS-1547对GH3活力的抑制也可通过Haloperidol（10μM）和PTX（100nM）得到挽救[6]。
在体内，MLS-1547（5mM; 0.5μL per side）通过双次双侧输注Sprague-Dawley大鼠内侧前额叶皮层mPFC，可显著降低大鼠在视觉线索引导的风险决策任务中的风险选择行为（较对照组平均降低14.941%），但不会影响大鼠对线索的识别能力，故MLS-1547在前额叶多巴胺系统中具有调节风险决策的潜力[7]。