Adenosine A2A antagonists with potent anti-cataleptic activity

Shimada, Junichi; Koike, Nobuaki; Nonaka, Hiromi; Shiozaki, Shizuo; Yanagawa, Koji; Kanda, Tomoyuki; Kobayashi, Hiroyuki; Ichimura, Michio; Nakamura, Junzo; Kase, Hiroshi; Suzuki, Fumio

doi:10.1016/s0960-894x(97)00440-x

Cited by 93 publications

(60 citation statements)

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“…46 KF-17837 is also reported to ameliorate motor deficits in experimental animals by virtue of antagonizing A 2A receptors. 106 Another xanthinyl derivative, CSC is commercially available and is used extensively as a reference A 2A antagonist in pharmacological studies.…”

Section: Methylxanthines As a 2a Antagonistsmentioning

confidence: 99%

“…43,44 A 2A antagonists also consistently enhance basal locomotor activity in unlesioned rodents, 45 as well as in animals rendered cataleptic with the dopamine receptor antagonist haloperidol. 46 These observations have led to clinical trials in PD patients with the caffeine-derived A 2A antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002) (2). 47,48 KW-6002 was shown to potentiate the symptomatic benefits conferred by a reduced dose of levodopa in relatively advanced PD and to produce motor enhancement that was comparable with that of an optimal levodopa dose.…”

Section: A 2a Receptors In the Cnsmentioning

confidence: 99%

“…103 Of particular importance was the discovery that substitution at C-8 with a styryl functional group yielded potent and selective A 2A antagonists. 24,46,102,103 Therefore, a large portion of the of reported A 2A antagonists are 1,3-dimethyl, 1,3-diethyl or 1,3-dipropyl substituted xanthinyl analogues bearing an (E)-8-styryl moiety modified on the phenyl ring.…”

Section: Methylxanthines As a 2a Antagonistsmentioning

confidence: 99%

“…27,110 This represents a limitation in the development of caffeine-derived, dualtarget-directed drugs because, in general, 1,3-diethyl substitution of the caffeine ring leads to enhanced A 2A antagonism. 25,46,110 Although 1, 3, and 7 methyl substitution is probably optimal for the design of xanthinebased reversible MAO-B inhibitors, ethyl or propyl functional groups at C-1 and C-3 are optimal for A 2A antagonism. Accordingly, the potent A 2A antagonist KW-6002 was found to be a relatively weak MAO-B inhibitor with a K i value of 28 M. 27 As for A 2A antagonists, 24 alkylation at N-7 of the xanthine ring is also a requirement for potent MAO-B inhibition (Table 4).…”

Section: Methylxanthines As Dual-target-directed Drugsmentioning

confidence: 99%

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Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Section: Methylxanthines As a 2a Antagonistsmentioning

confidence: 99%

Section: A 2a Receptors In the Cnsmentioning

confidence: 99%

Section: Methylxanthines As a 2a Antagonistsmentioning

confidence: 99%

Section: Methylxanthines As Dual-target-directed Drugsmentioning

confidence: 99%

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Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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“…Several adenosine A 2A antagonists have been used as labeling ligands with positron-emitting radioisotopes (15)(16)(17). Among these antagonists, xanthine derivatives had trouble with processes such as nonspecific binding and photoisomerization (18,19), whereas nonxanthine derivatives avoided these problems. 11 C-SCH442416 has been recently introduced as the first, to our knowledge, nonxanthine ligand suitable for in vivo imaging of adenosine A 2A R in PET because of the high affinity and selectivity to adenosine A 2A R of the compound, the good signal-to-noise ratios, and a low amount of radioactive metabolite in the brain of nonhuman primates (20).…”

mentioning

confidence: 99%

Brain Adenosine A_2A Receptor Occupancy by a Novel A₁/A_2A Receptor Antagonist, ASP5854, in Rhesus Monkeys: Relationship to Anticataleptic Effect

Mihara

Noda²,

Arai³

et al. 2008

J Nucl Med

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The purpose of the present study was to measure adenosine A 2A receptor (A 2A R) occupancy in the brain by a novel adenosine A 1 / A 2A antagonist, 5-[5-amino-3-(4fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), and to determine the degree of receptor occupancy necessary to inhibit haloperidolinduced catalepsy in rhesus monkeys. Methods: A 2A R occupancy by ASP5854 (0.001-0.1 mg/kg) was examined in the striatum using an A 2A R-specific radiotracer, 11 C-SCH442416, and PET in conscious rhesus monkeys. A 2A R occupancy was monitored after a single intravenous administration of ASP5854 in 3 animals, and a dynamic PET scan was performed at 1, 4, and 8 h after an intravenous bolus injection of the tracer for approximately 740 MBq. Catalepsy was induced by haloperidol (0.03 mg/kg, intramuscularly) and examined for incidence and duration. Results: ASP5854 dose-dependently increased A 2A R occupancy in the striatum and showed long-lasting occupancy even after the reduction of plasma concentration. Haloperidol induced severe catalepsy at 40 min after intramuscular injection. The incidence and duration of cataleptic posture were dose-dependently reduced by ASP5854 at 1 h after oral administration, and the minimum ED 50 value was 0.1 mg/kg. Administration of a dose of 0.1 mg/kg yielded a plasma concentration of 97 6 16.3 ng/mL, which corresponded to 85%-90% of A 2A R occupancy. Conclusion: These results showed that ASP5854 antagonized A 2A R in the striatum, and the dissociation from A 2A R was relatively slow. In addition, more than 85% A 2A R occupancy by ASP5854 resulted in an inhibition of haloperidol-induced catalepsy. Thus, such a pharmacodynamic study directly demonstrates both the kinetics of a drug in the brain and the relationship between dose-dependent receptor occupancy and plasma level. Adenosi ne A 2A receptors (A 2A Rs) are abundantly localized in the caudate-putamen, nucleus accumbens, and olfactory tubercle in several species (1). They are coexpressed with dopamine D 2 receptors in the GABAergic striatopallidal neurons; in contrast, there are no A 2A Rs in the neurons projecting from the striatum to the substantial nigra and expressing D 1 receptors (2,3). Stimulation of adenosine A 2A Rs decreases the binding affinity of D 2 receptors (4) and elicits effects opposite to the ones shown by D 2 receptor activation at the level of second-messenger systems and early gene expression (5,6). These observations suggest that antagonistic adenosine-dopamine interactions may be important in the regulation of the activity of the basal ganglia and could explain the depressant and stimulating effects of adenosine A 2A R agonists and antagonists on motor behavior (7).In addition, adenosine receptor agonists induce sedation and catalepsy dose-dependently and inhibit the motoractivating effects of dopamine receptor agonists (7,8). In contrast, adenosine receptor antagonists, including caffeine and related methylxanthines, produce motor-stimulant effects (9), which appear to be related to an action on A 2...

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A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand

Müller¹,

Sauer²,

Maurinsh³

et al. 1998

Drug Dev. Res.

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A2A adenosine receptor (AR) antagonists are promising new drugs for the treatment of Parkinson's disease. Further potential therapeutic indications for A2A AR antagonists include dementias, ischemias, and pain. Potent, selective A2A AR antagonists have been developed, but their generally low water solubility is a major problem for conducting in vivo experiments. We developed a water‐soluble phosphate prodrug (MSX‐3) of a potent, selective A2A AR antagonist (MSX‐2), which is stable in aqueous solution, but rapidly cleaved in vivo by phosphatases to release the active compound MSX‐2. Intracerebral application of MSX‐3 led to a stimulation of motor activity in rats. Catalepsy, induced by pretreatment with either dopamine D1 or D2 antagonist, was potently reversed by intracerebral application of MSX‐3. A new A2A‐selective antagonist radioligand, [3H]MSX‐2, was prepared, which exhibits a KD value of 8 Nm at rat brain striatal membranes. Drug Dev. Res. 45:190–197, 1998. © 1998 Wiley‐Liss, Inc.

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Adenosine A2A antagonists with potent anti-cataleptic activity

Cited by 93 publications

References 9 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Brain Adenosine A_2A Receptor Occupancy by a Novel A₁/A_2A Receptor Antagonist, ASP5854, in Rhesus Monkeys: Relationship to Anticataleptic Effect

A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand

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Adenosine A2A antagonists with potent anti-cataleptic activity

Cited by 93 publications

References 9 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Brain Adenosine A2A Receptor Occupancy by a Novel A1/A2A Receptor Antagonist, ASP5854, in Rhesus Monkeys: Relationship to Anticataleptic Effect

A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand

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Brain Adenosine A_2A Receptor Occupancy by a Novel A₁/A_2A Receptor Antagonist, ASP5854, in Rhesus Monkeys: Relationship to Anticataleptic Effect