SYN115 is a novel, selective adenosine A(2A) receptor antagonist. The selective adenosine A(2A) receptor antagonists have been proposed as therapeutic tools for dopaminergically-relevant diseases. Adenosine A(2a) receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. In cocaine-dependent subjects, SYN115 may produce stimulant-like effects through a unique mechanism of action. We conclude that SYN115 enters the brain and exerts dose-dependent regional effects, the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies.
|Cell lines||CHO cells|
|Preparation method||A1 and A2B adenosine receptor functional assay
CHO cells, expressing recombinant human ARs, were harvested by trypsinization. After centrifugation and re-suspension in medium, cells (~30,000) were plated in 24-well plates in 0.5 mL of medium. After 24 h, the medium was removed, and the cells were incubated at 37℃ for 15 min with 0.5 mL of Dulbecco's Modified Eagle Medium (DMEM) in the presence of adenosine deaminase (ADA) (1 U/mL) and the phosphodiesterase inhibitor Ro20-1724 (20 mM). The pharmacological profile of the compounds towards A2B ARs was evaluated by assessing cAMP accumulation in the absence or presence of the agonist NECA (100 nM). The antagonist profile of the compounds towards A1 ARs was evaluated by assessing their ability to counteract NECA-mediated inhibition of cAMP accumulation in the presence of 1 mM forskolin, as non-selective adenylate cyclase (AC) activator. Cells were incubated in the reaction medium (15 min at 37℃) with different concentrations of target compounds (0.1 nM~1 mM) and then were treated with the agonist. Following incubation, the reaction was terminated by the removal of the medium and the addition of 0.4 N HCl. After 30 min, lysates were neutralized with 4 N KOH, and the suspension was centrifuged at 800 g for 5 min. For the determination of cAMP production, bovine adrenal cAMP binding protein was incubated with [3H]cAMP (2 nM) and 50 ml of cell lysate or cAMP standard (0~160 pmol) at 0℃for 150 min in a total volume of 300 ml. Bound radioactivity was separated by rapid filtration through GF/C glass fiber filters and washed twice with 4 mL 50 mM TriseHCl, pH 7.4. The radioactivity was measured by liquid scintillation spectrometry.
|Incubation time||15 min|
|Animal models||male Swiss albino mice(23~25 g)|
|Formulation||isotonic (NaCl 0.9%) saline solution|
|Dosages||3, 10 and 30mg/kg was given immediately after punishment|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Further studies on pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective human A1 adenosine receptor antagonists.
Giovannoni MP, et al. Eur J Med Chem. 2015 Jan 7;89:32-41. PMID: 25462223.
Cardiovascular and Subjective Effects of the Novel Adenosine A(2A) Receptor Antagonist SYN115 in Cocaine Dependent Individuals.
Lane et al. J Addict Res Ther. 2012 Mar 28;S1. PMID: 22905331.
Increased Orbitofrontal Brain Activation after Administration of a Selective Adenosine A(2A) Antagonist in Cocaine Dependent Subjects.
Moeller et al. Front Psychiatry. 2012;3:44. PMID: 22654774.
Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease.
Black et al. J Neurosci. 2010 Dec 1;30(48):16284-92. PMID: 21123574.
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