Design and Synthesis of Novel Dual‐Action Compounds Targeting the Adenosine A_2A Receptor and Adenosine Transporter for Neuroprotection

Abstract

A novel compound, N⁶-(4-hydroxybenzyl)adenosine, isolated from Gastrodia elata and which has been shown to be a potential therapeutic agent for preventing and treating neurodegenerative disease, was found to target both the adenosine A(2A) receptor (A(2A) R) and the equilibrative nucleoside transporter 1 (ENT1). As A(2A) R and ENT1 are proximal in the synaptic crevice of striatum, where the mutant huntingtin aggregate is located, the dual-action compounds that concomitantly target these two membrane proteins may be beneficial for the therapy of Huntington's disease. To design the desired dual-action compounds, pharmacophore models of the A(2A) R agonists and the ENT1 inhibitors were constructed. Accordingly, potentially active compounds were designed and synthesized by chemical modification of adenosine, particularly at the N⁶ and C⁵' positions, if the predicted activity was within an acceptable range. Indeed, some of the designed compounds exhibit significant dual-action properties toward both A(2A) R and ENT1. Both pharmacophore models exhibit good statistical correlation between predicted and measured activities. In agreement with competitive ligand binding assay results, these compounds also prevent apoptosis in serum-deprived PC12 cells, rendering a crucial function in neuroprotection and potential utility in the treatment of neurodegenerative diseases.

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

“…In addition, our previously published articles show that a novel compound, N-(4-hydroxybenzyl)adenosine purified from Gastrodia elata [52], had A 2A -R-binding potency that exerted protection in treating R6/2 mice (an HD animal model) [53]. This compound may be a novel therapeutic drug and lead to the development of new drugs to treat other neurodegenerative diseases [31]. Therefore, regarding plant hormones, cytokinins, the application of zeatin riboside or others with A 2A -R-binding affinities may also be possibly implicated as novel neuroprotectants and leads for alternative treatments of neurodegeneration [25], [54].…”

“…According to our recently published pharmacophore models of the A 2A -R [31], the K i of some cytokinins were ranged from 2.9 to 46 µM (Supplement S1). We next tested their biological functions using a serum deprivation-induced cell death model that highlighted the functional role of the A 2A -R [30].…”

T1-11, an adenosine derivative, ameliorates aging-related behavioral physiology and senescence markers in aging mice

“…Currently, more than 81 compounds, including gastrodin, vanillin, gastrodigenin and parishins, were isolated and identified from this plant [ 27 ]. T1-11 is one of compounds from G. elata , which was found to prevent apoptosis in serum-deprived PC12 cells by suppressing JNK activity [ 10 , 28 ]. We also found that T1-11 could decrease D-gal-induced cell death ( Supplementary Figure 1E ).…”

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…Pharmacological blockade with the low affinity ENT1 inhibitor JMF1907 231 or genetic blockade of ENT (global ENT1 knockout) led to a significant increase in the mean survival time in the R6/2 mouse model of HD. 201 In the same study, there was also an increase in the expression and activity of both ENT1 and ENT2.…”

“…201,231 Given that inhibitors of ENT1 such as dipyridamole, ticagrelor, or dilazep are already being used to treat different pathological conditions related to vascular relaxation and platelet aggregation, and that the ENT1 inhibiting nonsteroidal anti-inflammatory drug sulindac sulfide is being used as an anti-inflammatory, it has been suggested that these compounds should be clinically studied in HD patients to evaluate their ability to delay the progression or the AAO of HD, even though some of these drugs have low brain penetrability. 233 The classical reserpinized mice model is a method that can be used to study specific antagonistic interactions between adenosine and dopamine receptor ligands and it led to the discovery of the A 2A R-D 2 R and A 1 R-D 1 R heteromers.…”