Guanfacine

Guanfacine is a selective, orally active norepinephrine α2A receptor agonist with high specificity for the α2A receptor subtype^[1-2]. By activating α2A-adrenergic receptors in the prefrontal cortex, Guanfacine inhibits excessive norepinephrine release, thereby enhancing prefrontal cortical function and improving cognitive abilities such as attention, impulse control, and behavioral planning^[3-4].

In vitro, incubation of P-glycoprotein-expressing LLC-PK1/MDR1 cells with Guanfacine (5μM and 50μM) for 60 minutes reduced P-glycoprotein levels^[5]. Treatment of human mesenchymal stem cell (hMSC)-derived 3D spheroids with Guanfacine (17.7ng/mL) for 21 days (chondrogenic differentiation) or 28 days (osteogenic differentiation), Guanfacine significantly suppressed the proteoglycan synthesis, and reducing calcium nodule formation^[6].

In vivo, a single intraperitoneal injection of Guanfacine (0.3–0.6mg/kg) in Wistar rats that had voluntarily consumed high amounts of alcohol (4.3 ± 0.2g/kg/24h; 5 months), Guanfacine significantly reduced 24-hour alcohol intake and attenuated alcohol deprivation effects as well as cue-induced alcohol-seeking behavior^[7]. Daily intraperitoneal administration of Guanfacine (0.1–0.3mg/kg) for 6 consecutive days in 3–4 month old male Nf1+/- mice significantly improved impulsive choice behavior and behavioral inhibition deficits^[8].

References:
[1] Arnsten AFT. Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species. Neurobiol Learn Mem. 2020 Dec;176:107327.
[2] Connor DF, Arnsten AF, Pearson GS, et al. Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. Expert Opin Pharmacother. 2014 Aug;15(11):1601-10..
[3] Rizzo R, Martino D. Guanfacine for the treatment of attention deficit hyperactivity disorder in children and adolescents. Expert Rev Neurother. 2015 Apr;15(4):347-54.
[4] Ota T, Yamamuro K, Okazaki K, et al. Evaluating Guanfacine Hydrochloride in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adult Patients: Design, Development and Place in Therapy. Drug Des Devel Ther. 2021 May 11;15:1965-1969.
[5] Gillis NK, Zhu HJ, Markowitz JS. An in vitro evaluation of guanfacine as a substrate for P-glycoprotein. Neuropsychiatr Dis Treat. 2011;7:501-5.
[6] Wagener N, Lehmann W, Böker KO, et al. Chondral/Desmal Osteogenesis in 3D Spheroids Sensitized by Psychostimulants. J Clin Med. 2022 Oct 21;11(20):6218.
[7] Fredriksson I, Jayaram-Lindström N, Wirf M, et al. Evaluation of guanfacine as a potential medication for alcohol use disorder in long-term drinking rats: behavioral and electrophysiological findings. Neuropsychopharmacology. 2015 Mar 13;40(5):1130-40.
[8] Lukkes JL, Drozd HP, Fitz SD, et al. Guanfacine treatment improves ADHD phenotypes of impulsivity and hyperactivity in a neurofibromatosis type 1 mouse model. J Neurodev Disord. 2020 Jan 15;12(1):2.

Guanfacine是一种选择性去甲肾上腺素能α2A受体激动剂，具有口服活性，对α2A受体亚型具有高度选择性^[1-2]。Guanfacine通过激活大脑前额叶皮质的α2A-肾上腺素受体，抑制去甲肾上腺素的过度释放，从而增强前额叶皮质的功能，改善注意力、冲动控制和行为规划等认知功能^[3-4]。

在体外，Guanfacine（5μM和50μM）在表达P-糖蛋白的LLC-PK1/MDR1细胞中孵育60分钟，可降低P-糖蛋白的水平^[5]。Guanfacine（17.7ng/mL）处理人间充质干细胞（hMSC）来源的3D球体21天（软骨分化）或28天（成骨分化），显著抑制蛋白聚糖合成，且减少钙结节形成^[6]。

在体内，Guanfacine（0.3–0.6mg/kg；单次注射）腹腔注射自愿摄入高酒精量（4.3±0.2g/kg/24h；5个月）的Wistar大鼠，显著降低其24小时酒精摄入量，并减弱酒精剥夺效应及线索/诱导复饮的酒精寻求行为^[7]。Guanfacine（0.1-0.3mg/kg）腹腔注射处理3-4月龄雄性Nf1+/-小鼠连续6天，显著改善小鼠的冲动选择行为和行为抑制缺陷^[8]。