Adenosine A _2A Receptor Antagonists in Neurodegenerative Diseases: Huge Potential and Huge Challenges

摘要

Background In this opinion paper, we provide scientific-based reasons about the huge therapeutic potential of adenosine A_(2A)receptor antagonists, and about the huge challenges to demonstrate efficacy in clinical trials, i.e., to provide data now required to approve a new medication by the regulatory bodies, such as U.S. Food and Drug Administration (FDA). Adenosine is an autacoid present in all tissue and body fluids. Adenosine, whose extracellular concentration is controlled by producing/degrading enzymes and by nucleoside transporters, acts via four (A_(1), A_(2A), A_(2B), and A_(3)) specific cell surface receptors that belong to the superfamily of G-protein-coupled receptors. For decades, adenosine receptors have shown promise as targets of medications for a variety of ailments. Until recently, however, the only approved medicine was adenosine itself, i.e., the endogenous agonist, to combat arrhythmias, such as paroxysmal supraventricular tachycardia ( 1 – 3 ). Prospects are changing as the first medication targeting selectively the adenosine A_(2A)receptor has been approved few years ago in Japan. The recently approved drug is an antagonist, i.e., a receptor blocker (see later). A_(2A)receptor antagonists show promise in neuroprotection, although for Huntington’s or Niemann Pick’s diseases it is suggested that antagonists may be detrimental and/or there is controversy on which is the efficacious intervention, i.e., receptor activation or blockade [see Ref. ( 4 – 9 ) and references therein]. Potential of A_(2A)Receptor Ligands in the Therapy of Neurodegenerative Diseases At present, not only the A_(2A)receptor (A_(2A)R) is at the center stage for increasing the therapeutic tools in a variety of clinical indications, but this opinion paper focuses on the A_(2A)R antagonists, which shows promise in immune-mediated control of cancer progression ( 10 – 13 ), in atrial fibrillation ( 14 , 15 ), and in fighting against neurodegenerative diseases (see later). It is relevant that virtually all the selective A_(2A)R antagonists whose toxicity has been tested in animal models are very safe. Safety has been confirmed in the clinical trials performed using different structures [e.g., Ref. ( 16 , 17 )]. Istradefylline (KW-6002) is one of the most studied antagonists; it is safe and efficacious in Parkinson’s disease. Accordingly, it was approved in Japan in 2013 for adjunctive treatment of Parkinson’s patients (under the Nouriast ?) ( 18 – 20 ). To our knowledge, up to five clinical trials with different antagonists were or are being undertaken ( 18 , 21 ), but none of them has yet got the approval by the U.S. FDA. In our opinion, the two main reasons of the difficulties in translating very promising preclinical assays into medications are (i) the tight requirements and (ii) the urgent need of efficacious approaches to assess neurodegenerationeuroprotection in humans. It is commented in drug discovery forums that quite a number of current drugs could not pass today the tight requirements posed by the regulatory bodies. The issue of assessing how to measure the neuroprotective efficacy of a drug is commented later. Parkinson’s and Alzheimer’s are the most extended neurodegenerative diseases in modern societies with high life expectancy ( 22 , 23 ). With some exceptions of early-onset symptoms ( 24 ), age is the main factor for triggering the clinical symptoms ( 25 – 28 ). Whereas, Parkinson’s disease patients have successful dopamine-replacement therapies and other tools that may be used in the disease progression or to decrease the appearance of the medication side effects ( 29 – 31 ), Alzheimer’s disease patients have not yet got any really efficacious therapeutic drug/tool ( 32 , 33 ). Clinical manifestation of Parkinson’s disease occurs when a significant number of nigral dopamine-producing neurons have disappeared. Natural aging leads to 18% of loss of tyrosine hydroxylase-positive neurons in the nigra, whereas the degree of denervation in patients is very wide, going from 50 to 90%, even shortly after diagnosis ( 34 ). In this study in post-mortem samples, the authors state: “ with several of the short-duration subjects showing comparable, severe loss of tyrosine hydroxylase-positive neurons to that seen in subjects 20?years, post-diagnosis ” ( 34 ). The idea behind the use of A_(2A)R antagonists in this disease is the adenosine-dopamine antagonism ( 35 – 37 ) in the striatum, where the expression of A_(2A)Rs is highest in the whole mammalian body ( 38 ). Therefore, dopamine-replacement therapy may be potentiated by the blockade of the A_(2A)R. Indeed, Nouriast? may serve to achieve efficacy of dopamine-replacement therapies at lower levels of dopaminergic drugs, such as levodopa. But the key point is that whereas levodopa is not neuroprotective, several preclinical assays indicate that A_(2A)R antagonists show neuroprotective effects [see Ref. ( 39 – 42 )]. Moreover, transgenic A_(2A)R animals are more res