(+)-AJ 76 hydrochloride is a dopamine receptors (DRs) antagonist [1] with preferential action at presynaptic receptors (pKi values are 6.95, 6.67, 6.37, 6.21 and 6.07 at hD3, hD4, hD2S, hD2L and rD2 receptors respectively). Dopamine is not only a neurotransmitter involved in motor, cognitive, and reward regulation, but it also plays an immunomodulatory role in the central and peripheral nervous systems[2]. (+)-AJ 76 hydrochloride can increase extracellular dopamine concentration by blocking presynaptic inhibitory receptors D2R and/or D3R on dopaminergic neuron terminals, which promotes dopamine transmission[3], and is therefore commonly used in neurology and studies of neurological related diseases such as Alzheimer's disease.
In vitro, (+)-AJ 76 hydrochloride (1μM) treatment of HEK 293 cells transfected with the D3 receptor for 35min reduced cellular phospholipase D (PLD) levels[4].
In vivo, MitoPark mice treated with intraperitoneal injection (+)-AJ 76 hydrochloride (20mg/kg) for 60 minutes significantly reduced the levels of DOPAC (3,4-Dihydroxyphenylacetic acid) in mouse cerebrospinal fluid and HVA (homovanillic acid) in mouse cerebrospinal fluid and plasma, suggesting that dopamine neuron challenge Test (DNC Test) using (+)-AJ 76 hydrochloride is helpful for early detection of PD (Parkinson’s disease)[5]. (+)-AJ 76 hydrochloride (300μmol/kg/day) fed to male Sprague-Dawley rats for 7 days increased voluntary activity activity and DOPAC levels in the striatum[6].
References:
[1] Svensson K, Johansson AM, Magnusson T, Carlsson A. (+)-AJ 76 and (+)-UH 232: central stimulants acting as preferential dopamine autoreceptor antagonists. Naunyn Schmiedebergs Arch Pharmacol. 1986 Nov;334(3):234-45. doi: 10.1007/BF00508777. PMID: 2880302.
[2] Channer, Breana et al. “Dopamine, Immunity, and Disease.” Pharmacological reviews vol. 75,1 (2023): 62-158. doi:10.1124/pharmrev.122.000618
[3] Waters N, Lagerkvist S, Löfberg L, Piercey M, Carlsson A. The dopamine D3 receptor and autoreceptor preferring antagonists (+)-AJ76 and (+)-UH232; a microdialysis study. Eur J Pharmacol. 1993 Sep 28;242(2):151-63. doi: 10.1016/0014-2999(93)90075-s. PMID: 8253112.
[4] Everett PB, Senogles SE. D3 dopamine receptor activates phospholipase D through a pertussis toxin-insensitive pathway. Neurosci Lett. 2004 Nov 16;371(1):34-9. doi: 10.1016/j.neulet.2004.08.033. PMID: 15500962.
[5] Zhou, Jingheng et al. “AJ76 and UH232 as potential agents for diagnosing early-stage Parkinson's disease.” Neuropharmacology vol. 226 (2023): 109397. doi:10.1016/j.neuropharm.2022.109397
[6] Kullingsjö H, Carlsson A, Svensson K. Effects of repeated administration of the preferential dopamine autoreceptor antagonist, (+)-AJ76, on locomotor activity and brain DA metabolism in the rat. Eur J Pharmacol. 1991 Dec 3;205(3):241-6. doi: 10.1016/0014-2999(91)90904-5. PMID: 1817961.
(+)-AJ 76 hydrochloride是一种对突触前受体具有优先作用的多巴胺受体（dopamine receptors, DRs）拮抗剂（hD3、hD4、hD2S、hD2L和rD2受体的pKi值分别为6.95、6.67、6.37、6.21和6.07）[1]。多巴胺不仅是一种参与运动、认知和奖励调节的神经递质，它在中枢神经系统和外周神经系统也起免疫调节的作用[2]。而(+)-AJ 76 hydrochloride可以通过阻断多巴胺能神经元末梢上突触前抑制性受体D2R和 (或) D3R，使得细胞外多巴胺浓度升高, 促进多巴胺的传递[3]，因此常用于神经学和阿尔兹海默症等神经相关疾病的研究。
在体外，(+)-AJ 76 hydrochloride（1μM）处理转染D3受体的HEK 293细胞35min，可降低细胞磷脂酶D（phospholipase D，PLD）的水平[4]。
在体内，(+)-AJ 76 hydrochloride（20mg/kg）腹腔注射处理MitoPark mice小鼠60分钟，显著降低了小鼠脑脊液中3,4-二羟基苯乙酸（3,4-Dihydroxyphenylacetic acid, DOPAC）和小鼠脑脊液和血浆中高香草酸（homovanillic acid, HVA）的水平，揭示使用(+)-AJ 76 hydrochloride的多巴胺神经元挑战试验（Dopamine Neuron Challenge Test, DNC Test）有助于帕金森病（Parkinson’s disease , PD）的早期检测[5]。(+)-AJ 76 hydrochloride（300μmol/kg/day）喂食雄性Sprague-Dawley大鼠7天，可以提高大鼠纹状体的自主活动活动和DOPAC水平[6]。