SCH 58261

SCH 58261 is the adenosine A2A receptor competitive antagonist. Displays 323-, 53- and 100-fold selectivity over A1, A2B and A3 receptors, respectively. target: adenosine A2A receptor IC50: 15 nM [3] in vitro: NK cells were cultured in NK cell media and preincubated with or without 1 uM SCH58261 30 min before simulation with indicated concentrations of IL-18 (R & D Systems) and IL-12p70 (Australian Biosearch) in the presence or absence of NECA (1 uM) or CGS-21680 (100 nM).[1] in vivo: it was demonstrated that the selective antagonist of the A2Areceptor, SCH58261, administered i.p. starting from the early minutes after ischemia induction, reduces ischemic brain damage and neurological deficit 24 h thereafter. vehicle-rats received saline with Tween 80 (1 %) administered (i.p.) .SCH58261 (0.01 mg/kg, i.p.), administered twice/day for 7 days [2]

References:
[1]. Paul A. Beavis et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci U S A, 2013 Sep 3, 110(36): 14711-14716. [2]. Alessia Melani et al. Time-course of protection by the selective A2Areceptor antagonist SCH58261 after transient focal cerebral ischemia. Neurological Sciences, August 2015, Volume 36, Issue 8, pp 1441-1448. [3]. Varani K et al. Pharmacological and biochemical characterization of purified A2a adenosine receptors in human platelet membranes by [3H]-CGS 21680 binding. Br J Pharmacol, 1996 Apr;117(8):1693-701.

Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective adenosine A2A receptor antagonists.[Pubmed:18562199]

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4199-203.

SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.

Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists.[Pubmed:18558486]

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4204-9.

SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.

Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease mice.[Pubmed:17720507]

Neurobiol Dis. 2007 Nov;28(2):197-205.

The effect of chronic treatment with the selective adenosine A2A receptor antagonist SCH 58261 on the behavioral and electrophysiological alterations typical of R6/2 mice (a transgenic mouse model of Huntington's disease, HD), has been studied. Starting from 5 weeks of age, R6/2 and wild type (WT) mice were treated daily with SCH 58261 (0.01 mg/kg i.p.) for 7 days. In the following weeks, the ability of mice to perform in the rotarod, plus maze and open field tests were evaluated. In addition, with electrophysiological experiments in corticostriatal slices we tested whether the well-known increased NMDA vulnerability of R6/2 mice was prevented by SCH 58261 treatment. We found that chronic treatment with SCH 58262: i) fully prevented the alterations in emotional/anxious responses displayed by R6/2 mice; ii) did not prevent the impairment in motor coordination; iii) abolished the increase in NMDA-induced toxicity observed in the striatum of HD mice. On balance, targeting A2A receptors seems to have some beneficial effects in HD even though, given the complexity of A2A receptor pharmacology and HD pathogenesis, further studies are necessary to clarify whether A2A receptor antagonists have therapeutic potential in HD.

The selective A2A receptor antagonist SCH 58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia.[Pubmed:16443200]

Brain Res. 2006 Feb 16;1073-1074:470-80.

We investigated the protective effect of subchronic treatment of the A2A receptor antagonist, SCH 58261 (0.01 mg/kg, i.p.), administered 5 min, 6 h and 15 h after permanent right middle cerebral artery occlusion (MCAo). Twenty-four hours after ischemia, an extensive pallid area, evaluated by cresyl violet staining, is evident in the vascular territories supplied by the MCA, the striatum and the sensory motor cortex. The pallid area reflects the extent of necrotic neurons. Soon after waking, rats showed a definite contralateral turning behavior which was significantly reduced by SCH 58261 treatment. Twenty-four hours after MCAo, SCH 58261 significantly improved the neurological deficit and reduced ischemic damage in the striatum and cortex. Phospho-p38 mitogen-activated protein kinase (MAPK), evaluated by Western Blot, increased by 500% in the ischemic striatum 24 h after MCAo. SCH 58261 treatment significantly reduced phospho-p38 MAPK by 70%. Microglia was immunostained using the OX-42 antibody. Phospho-p38 MAPK and OX-42-immunoreactive cells are localized in the ventral striatum and frontoparietal cortex. Furthermore, both OX-42 and phospho-p38 MAPK-immunoreactive cells have overlapping morphological features, typical of reactive microglia. SCH 58261 reduced phospho-p38 MAPK immunoreactivity in the striatum and in the cortex without changing the microglial cell morphology. These results indicate that the protective effect of the adenosine antagonist SCH 58261 during ischemia is not due to reduced microglial activation but involves inhibition of phospho-p38 MAPK and suggest that treatment with the A2A antagonist from the first hour to several hours after ischemia may be a useful therapeutic approach in cerebral ischemia.

Effects of A(1) and A(2A) adenosine receptor ligands in mouse acute models of pain.[Pubmed:12147316]

Neurosci Lett. 2002 Aug 16;328(3):241-4.

The effects of selective A(1) and A(2A) adenosine receptor compounds in two mouse models of acute nociception were studied: acetic acid-induced writhing and the hot plate assays. Stimulation of A(1) receptors by 2-chloro-N(6)-cyclopentyl-adenosine (CCPA, 0.01-0.1 mg/kg, i.p.; A(1)K(i)=6 nM) or blockade of A(2A) receptors by 5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyri midine (SCH58261, 1-10 mg/kg, i.p.; A(2)(A)K(i)=1.3 nM) produced anti-nociceptive effects. At the highest dose tested, CCPA and SCH58261 reduced the number of writhings by 79 and 99%, respectively. On the contrary, the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (A(1)K(i)=2.8 nM) and the A(2A) agonist 2-(4-[2-carboxyethyl])phenethylamino-5'-N-ethylcarboxamido-adenosine-hydrochlorid e (GGS21680) produced pro-nociceptive effects in both tests. These findings suggest for the first time that blockade of A(2A) adenosine receptors produces anti-nociceptive effects.

The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2a adenosine receptor antagonist.[Pubmed:8632302]

J Pharmacol Exp Ther. 1996 Feb;276(2):398-404.

We have characterized the in vitro pharmacological profile of the new potent and selective A2a adenosine receptor antagonist SCH 58261 [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine]. In binding studies on rat and bovine brain tissues, SCH 58261 showed affinity in the low nanomolar range at A2a adenosine striatal receptors and good A2a adenosine vs. A1 adenosine selectivity (about 50- to 100-fold in rat and bovine brain, respectively). SCH 58261 did not show affinity for either the A3 adenosine receptor or other receptors at concentrations up to 1 microM. Saturation experiments on rat A1 and A2a adenosine receptors indicated the competitive nature of the antagonism. SCH 58261 antagonized competitively the effects induced by the A2a adenosine-selective agonist CGS 21680 (2-[4-(2-carboxyethyl)-phenethyl-amino]-5'-N- ethylcarboxamidoadenosine) in two functional assays, such as inhibition of rabbit platelet aggregation and porcine coronary artery relaxation. Specifically, the compound showed pA2 values of 7.9 and 9.5, respectively. SCH 58261 (300 nM) failed to antagonize 5'-N-ethylcarboxamidoadenosine-induced vasorelaxation in the isolated guinea pig aorta, a response mediated by A2b adenosine receptors. Likewise, at the same concentration, the compound weakly inhibited the A1 adenosine-mediated negative chronotropic effect induced by 2-chloro-N6-cyclopentyladenosine in the isolated rat atria. These data show that SCH 58261 is a potent and selective non-xanthine A2a adenosine antagonist which has competitive properties in biological responses mediated by this receptor subtype. The compound is of interest for investigating the biological role of A2a adenosine receptors and deserves further attention to clarify the therapeutic potential of A2a antagonists.

SCH 58261 is a potent, selective and competitive antagonist of adenosine A2A receptor with an IC50 of 15 nM, and displays 323-, 53- and 100-fold more selective for A2A receptor than A1, A2B, and A3 receptors, respectively.

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