Adenosine A_2A Receptor Antagonists and Parkinson’s Disease

Abstract

P arkinson's disease (PD) is a chronic, progressive neurologicaldisease that affects ∼1% of the population over the age of 65. 1 It is characterized by progressive impairment in motor function that is often accompanied by disturbances in mood and cognitive function. The majority of motor impairments of PD are caused by a gradual loss of dopamine (DA) producing neurons in the ventral midbrain and concomitant loss of DA input to forebrain (striatal) motor structures. 2,3 The loss of DA input to the neostriatum leads to dysregulation of striatal function and the classic motor symptoms of PD, such as resting tremor, muscular rigidity, and bradykinesia.The majority of treatments aim to restore dopamine signaling and thereby reduce the severity of the motor symptoms. Dopamine replacement therapy using L-DOPA, the precursor to dopamine, remains the gold-standard treatment for PD. Other approaches include inhibition of DA turnover using monoamine oxidase type B (MAO-B) inhibitors, 4 catechol O-methyl-transferase (COMT) inhibitors, 5 and inhibition of dopamine reuptake 6 or direct agonists 7 of postsynaptic dopamine receptors. Although the dopamine targeted therapies work well to address the PD related motor disturbances, they all produce undesirable side effects (dyskinesia, hallucinations, onÀoff effects) that become more severe and problematic with continued treatment. Also, the aforementioned therapies typically show reduced efficacy as motor functions deteriorate and the disease progresses. Moreover, these treatments do not alter disease progression and do not address the mood, postural instability, or cognitive disturbances that frequently accompany PD.The dopamine replacement agents have significant limitations which influenced researchers to find nondopamine based treatments for PD. One nondopaminergic approach that has received considerable attention is modulation of adenosine receptors which is the topic highlighted in this Review. 8 Adenosine is a neuromodulator that coordinates responses to dopamine and other neurotransmitters in areas of the brain that are responsible for motor function, mood, and learning and memory. 9 Adenosine comprises four distinct receptor subtypes designated A 1 , A 2A , A 2B , and A 3 belonging to the G protein-coupled receptor superfamily. 10 Adenosine A 1 and A 3 receptors are coupled to inhibitory G proteins, while A 2A and A 2B receptors are coupled to stimulatory G proteins. Autoradiography studies in rodents showed that the greatest densities of A 2A receptors are found in the striatum 11 which closely matches the distribution in humans based on PET imaging. 12 As described above, loss of dopamine input into the neostriatum is a hallmark of PD and causes many of the cardinal motor symptoms of this disorder. In the striatum adenosine A 2A receptors colocalize and physically associate with dopamine D 2 receptors. ABSTRACT: This Review summarizes and updates the work on adenosine A 2A receptor antagonists for Parkinson's disease from 2006 to the present. There have been numerou...

Crystal structure of the adenosine A 2A receptor bound to an antagonist reveals a potential allosteric pocket

“…As a member of the G protein-coupled receptor (GPCR) family, the A 2A receptor couples to stimulatory G protein G s and elevates intracellular cAMP upon activation by endogenous adenosine. The A 2A R has been an attractive drug target due to its role in cardiovascular and immune system function, as well as in the central nervous system as a potential therapeutic target for Parkinson's disease (PD) (1)(2)(3)(4). PD is a neurodegenerative disease that affects more than 1% of the population over 65 years old.…”

“…Currently, major treatments target the restoration of dopamine signaling, which is impaired in PD patients, by dopamine-replacing agents. Although these treatments effectively address PD-related motor disturbances, the long-term use of dopamine-replacing agents is associated with the development of motor complications; therefore, there is a need for nondopaminergic drugs (2). It is known that A 2A R signaling regulates dopaminergic neurotransmission, and A 2A R antagonists have been shown to enhance D2 dopamine receptor signaling, which has been found to improve PD symptoms in animal models and patients, without the side effects common to dopaminereplacing agents, such as dyskinesia (1,5).…”

Evaluation of 2‐benzylidene‐1‐tetralone derivatives as antagonists of A1 and A2A adenosine receptors

“…[19] Furthermore, a dual-target A 1 /A 2A AR antagonist may have a synergistic motor activating effect; antagonism of the A 1 AR facilitates presynaptic dopamine release and antagonism of the A 2A AR facilitates postsynaptic dopamine release. [24] For example, the motor activating effect of caffeine ( Figure 1) may be due to the synergistic activity of antagonizing both the A 1 and A 2A ARs. [25] Affinity for both the A 1 and A 2A ARs were found for selected aurone derivatives.…”

1,3,7-Triethyl-substituted xanthines—possess nanomolar affinity for the adenosine A1 receptor

“…Adenosine A 1 receptors are expressed presynaptically in the striatum on both glutamatergic and dopaminergic neurons, 9,14,17 whereas adenosine A 2A receptors are concentrated mainly in the striatum and co-localized with dopamine D 2 receptors. 17 Adenosine A 2A receptor antagonists may improve PD-related motor impairment 18 via the blockade of adenosine A 2A receptors by facilitating dopamine receptor signaling and thereby restoring motor function in animal models of PD. 19 Additionally, blockade of the adenosine A 2A receptors also exerts neuroprotective effects.…”

“…21 Antagonism of both adenosine A 1 and A 2A receptors results in a synergistic motor activating effect, where inhibition of the adenosine A 1 receptor facilitates presynaptic dopamine release, whereas inhibition of the adenosine A 2A receptor enhances postsynaptic responses to dopamine. 17 Compared to the motor symptoms, the PD-related non-motor symptoms are under-recognized clinically and as a result undertreated. 22 This may be partly due to evidence suggesting that non-motor symptoms do not respond to dopaminergic replacement therapy.…”