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Simon M. Poucher - One of the best experts on this subject based on the ideXlab platform.

  • the role of the a 2a Adenosine Receptor subtype in functional hyperaemia in the hindlimb of anaesthetized cats
    The Journal of Physiology, 1996
    Co-Authors: Simon M. Poucher
    Abstract:

    1. The present study was designed to investigate the contribution of the A(2A) Adenosine Receptor subtype in the functional hyperaemia response during muscle contraction. 2. In cats anaesthetized with sodium pentobarbitone and breathing spontaneously following tracheotomy, the left sciatic and femoral nerves were electrically stimulated at 3 Hz for 20 min to induce muscle contraction, and hindlimb blood flow was measured with a flow probe. The contribution of the A(2A) Adenosine Receptor subtype was assessed using ZM 241385, a potent and selective A(2A) Adenosine Receptor Antagonist. 3. In a control group, the muscle isometric tension measured in the extensor digitorum longus-tibialis anterior muscle group was 6.64 +/- 0.66 kg (100 g muscle mass)(-1) and hindlimb vascular conductance was 0.22 +/- 0.03 ml mmHg(-1)(kg body mass)(-1) at 20 min of contraction. Administration of vehicle did not affect these parameters upon a second contraction period: 6.31 +/- 0.61 kg (100 g muscle mass)(-1) and 0.23 +/- 0.03 ml mmHg(-1) (kg body mass)(-1), respectively. Total hindlimb conductance during contraction was unaffected (5.5 +/- 3.7% decrease). 4. ZM 241385 (1.0 mg kg(-1)) did not alter the amount of force produced by the muscle at 20 min of contraction. Hindlimb conductance response was reduced by 27.1 +/- 4.8% following the A(2A) selective Adenosine Receptor Antagonist, similar to that observed with the non-selective Antagonist 8-phenyltheophylline. 5. These results show that Adenosine acting at the A(2A) subtype Receptor can contribute up to 30% of the functional hyperaemia response in the hindlimb of anaesthetized cats.

  • Pharmacodynamics of ZM 241385, a Potent A2a Adenosine Receptor Antagonist, after Enteric Administration in Rat, Cat and Dog
    The Journal of pharmacy and pharmacology, 1996
    Co-Authors: Simon M. Poucher, J.r. Keddie, R. Brooks, G. R. Shaw, D. Mckillop
    Abstract:

    4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A 2a Adenosine Receptor Antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1-10 mg kg -1 ) selectively attenuated the mean arterial blood pressure response produced by exogenous Adenosine (1 mg kg -1 min -1 , i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg -1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to Adenosine (0.6-1.0 mg kg -1 , i.v.) by 94% after 10 mg kg -1 (p.o.) and by up to 74% after 0.3 mg kg -1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg -1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1-10 mg kg -1 ), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg -1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg -1 ) attenuation of the vasodilatation responses to Adenosine Receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A 2a Adenosine Receptor Antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of Adenosine A 2a Receptors in the action of Adenosine in-vivo.

  • the in vitro pharmacology of zm 241385 a potent non xanthine a2a selective Adenosine Receptor Antagonist
    British Journal of Pharmacology, 1995
    Co-Authors: Simon M. Poucher, J.r. Keddie, Pirthipal Singh, S M Stoggall, P W R Caulkett, G Jones, M G Collis
    Abstract:

    Abstract 1. This paper describes the in vitro pharmacology of ZM 241385 (4-(2-[7-amino-2-(2-furyl) [1,2,4]-triazolo[2,3-a][1,3,5]triazin- 5-yl amino]ethyl) phenol), a novel non-xanthine Adenosine Receptor Antagonist with selectivity for the A2a Receptor subtype. 2. ZM 241385 had high affinity for A2a Receptors. In rat phaeochromocytoma cell membranes, ZM 241385 displaced binding of tritiated 5'-N-ethylcarboxamidoAdenosine (NECA) with a pIC50 of 9.52, (95% confidence limits, c.l., 9.02-10.02). In guinea-pig isolated Langendorff hearts, ZM 241385 antagonized vasodilatation of the coronary bed produced by 2-chloroAdenosine (2-CADO) and 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoAdenosine (CGS21680) with pA2 values of 8.57 (c.l., 8.45-8.68) and 9.02 (c.l., 8.79-9.24) respectively. 3. ZM 241385 had low potency at A2b Receptors and antagonized the relaxant effects of Adenosine in the guinea-pig aorta with a pA2 of 7.06, (c.l., 6.92-7.19). 4. ZM 241385 had a low affinity at A1 Receptors. In rat cerebral cortex membranes it displaced tritiated R-phenylisopropylAdenosine (R-PIA) with a pIC50 of 5.69 (c.l., 5.57-5.81). ZM 241385 antagonized the bradycardic action of 2-CADO in guinea-pig atria with a pA2 of 5.95 (c.l., 5.72-6.18). 5. ZM 241385 had low affinity for A3 Receptors. At cloned rat A3 Receptors expressed in chinese hamster ovary cells, it displaced iodinated aminobenzyl-5'-N-methylcarboxamido Adenosine (AB-MECA) with a pIC50 of 3.82 (c.l., 3.67-4.06). 6. ZM 241385 had no significant additional pharmacological effects on the isolated tissues used in these studies at concentrations three orders of magnitude greater than those which block A2a Receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Silvio Dionisotti - One of the best experts on this subject based on the ideXlab platform.

  • binding of the radioligand 3h sch 58261 a new non xanthine a2a Adenosine Receptor Antagonist to rat striatal membranes
    British Journal of Pharmacology, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Ennio Ongini, Silvia Ferrara, Silvio Dionisotti
    Abstract:

    1. The present study describes the binding to rat striatal A2A Adenosine Receptors of the new potent and selective Antagonist radioligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazol o [1,5-c] pyrimidine, [3H]-SCH 58261. 2. [3H]-SCH 58261 specific binding to rat striatal membranes ( > 90%) was saturable, reversible and dependent upon protein concentration. Saturation experiments revealed that [3H]-SCH 58261 labelled a single class of recognition sites with high affinity (Kd = 0.70 nM) and limited capacity (apparent Bmax = 971 fmol mg-1 of protein). The presence of 100 microM GTP in the incubation mixture did not modify [3H]-SCH 58261 binding parameters. 3. Competition experiments showed that [3H]-SCH 58261 binding is consistent with the labelling of A2A striatal Receptors. Adenosine Receptor agonists competed with the binding of 0.2 nM [3H]-SCH 58261 with the following order of potency: 2-hexynyl-5'-N-ethyl carboxamidoAdenosine (2HE-NECA) > 5'-N-ethylcarboxamidoAdenosine (NECA) > 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne (CGS 21680) > 2-phenylaminoAdenosine (CV 1808) > R-N6-phenylisopropylAdenosine (R-PIA) > N6-cyclohexylAdenosine (CHA) = 2-chloro-N6-cyclopentylAdenosine (CCPA) > S-N6-phenylisopropylAdenosine (S-PIA). 4. Adenosine Antagonists inhibited [3H]-SCH 58261 binding with the following order: 5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo[1,5-c] quinazoline (CGS 15943) > 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine (8FB-PTP) = SCH 58261 > xanthine amine congener (XAC) = (E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837S) > 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) > or = 8-phenyltheophylline (8-PT). 5. The Ki values for Adenosine Antagonists were similar to those labelled with the A2A agonist [3H]-CGS 21680. Affinities of agonists were generally lower. The A1-selective agonist, R-PIA, was found to be about 9 fold more potent than its stereoisomer, S-PIA, thus showing the stereoselectivity of [3H]-SCH 58261 binding. Except for 8-PT, the Adenosine agonists and Antagonists examined inhibited [3H]-SCH 58261 binding with Hill coefficients not significantly different from unity. 6. The present results indicate that [3H]-SCH 58261 is the first non-xanthine Adenosine Antagonist radioligand which directly labels A2A striatal Receptors. High Receptor affinity, good selectivity and very low non-specific binding make [3H]-SCH 58261 an excellent probe for studying the A2A Adenosine Receptor subtype in mammalian brain.

  • the non xanthine heterocyclic compound sch 58261 is a new potent and selective a2a Adenosine Receptor Antagonist
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Angela Monopoli, Ennio Ongini, A Conti, A Negretti, Silvio Dionisotti
    Abstract:

    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]-59-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 59-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.

Ennio Ongini - One of the best experts on this subject based on the ideXlab platform.

  • cardiovascular pharmacology of the a2a Adenosine Receptor Antagonist sch 58261 in the rat
    Journal of Pharmacology and Experimental Therapeutics, 1998
    Co-Authors: Angela Monopoli, Carlo Casati, Gianluca Lozza, A Forlani, Ennio Ongini
    Abstract:

    We characterized the in vivo cardiovascular profile of SCH 58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c] pyrimidine, a selective A2A Adenosine Receptor Antagonist, in conscious, freely moving rats by use of the telemetry system. In normotensive rats, SCH 58261, at 10 mg/kg i.p., significantly (P < .05) inhibited hypotension and tachycardia induced by the A2A Receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoAdenosine (0.01 mg/kg i.p.), but not the bradycardic effect caused by the A1 Receptor agonist 2-chloro-N6-cyclopentylAdenosine (0.03 mg/kg i.p.). SCH 58261, when administered alone, at 0.1 and 1 mg/kg i.p., did not induce significant hemodynamic changes, but at 10 mg/kg i.p., it slightly increased both systolic blood pressure (SBP) and diastolic blood pressure (DBP) (+19 +/- 3 and +16 +/- 2 mm Hg, respectively; P < . 01) and heart rate (HR) (+85 +/- 5 beats/min; P < .01). These effects were inhibited by adrenergic blockade with propranolol (30 mg/kg i.p.) and phentolamine (10 mg/kg i.p.): -5 +/- 3 mm Hg on DBP and -12 +/- 11 beats/min on HR (P < .01). In spontaneously hypertensive rats, SCH 58261, at 3 and 10 mg/kg i.p., increased weakly both SBP (+19 +/- 5 mm Hg and +25 +/- 4 mm Hg) and DBP (+14 +/- 4 mm Hg and +23 +/- 4 mm Hg) vs. vehicle (P < .01) and HR (+45 +/- 17 and +64 +/- 18 beats/min vs. vehicle, respectively; P < .01). The data indicate that SCH 58261 retains A2A selective Receptor Antagonist properties in vivo. Its effect on cardiovascular sympathetic outflow further suggests that endogenous Adenosine exerts a tonic vascular regulation through A2A Receptors. Therefore, SCH 58261 can be a useful pharmacological tool for clarifying A2A-mediated cardiovascular actions of Adenosine.

  • binding of the radioligand 3h sch 58261 a new non xanthine a2a Adenosine Receptor Antagonist to rat striatal membranes
    British Journal of Pharmacology, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Ennio Ongini, Silvia Ferrara, Silvio Dionisotti
    Abstract:

    1. The present study describes the binding to rat striatal A2A Adenosine Receptors of the new potent and selective Antagonist radioligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazol o [1,5-c] pyrimidine, [3H]-SCH 58261. 2. [3H]-SCH 58261 specific binding to rat striatal membranes ( > 90%) was saturable, reversible and dependent upon protein concentration. Saturation experiments revealed that [3H]-SCH 58261 labelled a single class of recognition sites with high affinity (Kd = 0.70 nM) and limited capacity (apparent Bmax = 971 fmol mg-1 of protein). The presence of 100 microM GTP in the incubation mixture did not modify [3H]-SCH 58261 binding parameters. 3. Competition experiments showed that [3H]-SCH 58261 binding is consistent with the labelling of A2A striatal Receptors. Adenosine Receptor agonists competed with the binding of 0.2 nM [3H]-SCH 58261 with the following order of potency: 2-hexynyl-5'-N-ethyl carboxamidoAdenosine (2HE-NECA) > 5'-N-ethylcarboxamidoAdenosine (NECA) > 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne (CGS 21680) > 2-phenylaminoAdenosine (CV 1808) > R-N6-phenylisopropylAdenosine (R-PIA) > N6-cyclohexylAdenosine (CHA) = 2-chloro-N6-cyclopentylAdenosine (CCPA) > S-N6-phenylisopropylAdenosine (S-PIA). 4. Adenosine Antagonists inhibited [3H]-SCH 58261 binding with the following order: 5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo[1,5-c] quinazoline (CGS 15943) > 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine (8FB-PTP) = SCH 58261 > xanthine amine congener (XAC) = (E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837S) > 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) > or = 8-phenyltheophylline (8-PT). 5. The Ki values for Adenosine Antagonists were similar to those labelled with the A2A agonist [3H]-CGS 21680. Affinities of agonists were generally lower. The A1-selective agonist, R-PIA, was found to be about 9 fold more potent than its stereoisomer, S-PIA, thus showing the stereoselectivity of [3H]-SCH 58261 binding. Except for 8-PT, the Adenosine agonists and Antagonists examined inhibited [3H]-SCH 58261 binding with Hill coefficients not significantly different from unity. 6. The present results indicate that [3H]-SCH 58261 is the first non-xanthine Adenosine Antagonist radioligand which directly labels A2A striatal Receptors. High Receptor affinity, good selectivity and very low non-specific binding make [3H]-SCH 58261 an excellent probe for studying the A2A Adenosine Receptor subtype in mammalian brain.

  • the non xanthine heterocyclic compound sch 58261 is a new potent and selective a2a Adenosine Receptor Antagonist
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Angela Monopoli, Ennio Ongini, A Conti, A Negretti, Silvio Dionisotti
    Abstract:

    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]-59-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 59-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.

Pier Giovanni Baraldi - One of the best experts on this subject based on the ideXlab platform.

  • novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl xanthines as potent and selective a2b Adenosine Receptor Antagonists
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser Zaid
    Abstract:

    Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 Antagonists of the A2B Adenosine Receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B Adenosine Receptor Antagonist activity. On the basis of these and previous results on the potent Antagonist effect of 8-pyrazolyl-xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B Receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified s...

  • synthesis biological properties and molecular modeling investigation of the first potent selective and water soluble human a3 Adenosine Receptor Antagonist
    Journal of Medicinal Chemistry, 2002
    Co-Authors: Anna Maconi, Pier Giovanni Baraldi, Kenneth A. Jacobson, Giorgia Pastorin, Tatiana Da Ros, Giampiero Spalluto, Zhanguo Gao, Barbara Cacciari, Katia Varani, Stefano Moro
    Abstract:

    A new, highly potent, selective, and water-soluble Antagonist of the hA3 Adenosine Receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (15 mM) and the highest affinity (Ki = 0.01 nM) and selectivity for the hA3 versus A1, A2A, and A2B Receptors (>10000-fold) ever reported. A Schild analysis of the antagonism by 4 of agonist-induced inhibition of cAMP production in CHO cells expressing the hA3 Receptor indicated a KB value of 0.20 nM.

  • binding of the radioligand 3h sch 58261 a new non xanthine a2a Adenosine Receptor Antagonist to rat striatal membranes
    British Journal of Pharmacology, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Ennio Ongini, Silvia Ferrara, Silvio Dionisotti
    Abstract:

    1. The present study describes the binding to rat striatal A2A Adenosine Receptors of the new potent and selective Antagonist radioligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazol o [1,5-c] pyrimidine, [3H]-SCH 58261. 2. [3H]-SCH 58261 specific binding to rat striatal membranes ( > 90%) was saturable, reversible and dependent upon protein concentration. Saturation experiments revealed that [3H]-SCH 58261 labelled a single class of recognition sites with high affinity (Kd = 0.70 nM) and limited capacity (apparent Bmax = 971 fmol mg-1 of protein). The presence of 100 microM GTP in the incubation mixture did not modify [3H]-SCH 58261 binding parameters. 3. Competition experiments showed that [3H]-SCH 58261 binding is consistent with the labelling of A2A striatal Receptors. Adenosine Receptor agonists competed with the binding of 0.2 nM [3H]-SCH 58261 with the following order of potency: 2-hexynyl-5'-N-ethyl carboxamidoAdenosine (2HE-NECA) > 5'-N-ethylcarboxamidoAdenosine (NECA) > 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne (CGS 21680) > 2-phenylaminoAdenosine (CV 1808) > R-N6-phenylisopropylAdenosine (R-PIA) > N6-cyclohexylAdenosine (CHA) = 2-chloro-N6-cyclopentylAdenosine (CCPA) > S-N6-phenylisopropylAdenosine (S-PIA). 4. Adenosine Antagonists inhibited [3H]-SCH 58261 binding with the following order: 5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo[1,5-c] quinazoline (CGS 15943) > 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine (8FB-PTP) = SCH 58261 > xanthine amine congener (XAC) = (E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837S) > 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) > or = 8-phenyltheophylline (8-PT). 5. The Ki values for Adenosine Antagonists were similar to those labelled with the A2A agonist [3H]-CGS 21680. Affinities of agonists were generally lower. The A1-selective agonist, R-PIA, was found to be about 9 fold more potent than its stereoisomer, S-PIA, thus showing the stereoselectivity of [3H]-SCH 58261 binding. Except for 8-PT, the Adenosine agonists and Antagonists examined inhibited [3H]-SCH 58261 binding with Hill coefficients not significantly different from unity. 6. The present results indicate that [3H]-SCH 58261 is the first non-xanthine Adenosine Antagonist radioligand which directly labels A2A striatal Receptors. High Receptor affinity, good selectivity and very low non-specific binding make [3H]-SCH 58261 an excellent probe for studying the A2A Adenosine Receptor subtype in mammalian brain.

  • the non xanthine heterocyclic compound sch 58261 is a new potent and selective a2a Adenosine Receptor Antagonist
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Angela Monopoli, Ennio Ongini, A Conti, A Negretti, Silvio Dionisotti
    Abstract:

    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]-59-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 59-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.

C Zocchi - One of the best experts on this subject based on the ideXlab platform.

  • binding of the radioligand 3h sch 58261 a new non xanthine a2a Adenosine Receptor Antagonist to rat striatal membranes
    British Journal of Pharmacology, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Ennio Ongini, Silvia Ferrara, Silvio Dionisotti
    Abstract:

    1. The present study describes the binding to rat striatal A2A Adenosine Receptors of the new potent and selective Antagonist radioligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazol o [1,5-c] pyrimidine, [3H]-SCH 58261. 2. [3H]-SCH 58261 specific binding to rat striatal membranes ( > 90%) was saturable, reversible and dependent upon protein concentration. Saturation experiments revealed that [3H]-SCH 58261 labelled a single class of recognition sites with high affinity (Kd = 0.70 nM) and limited capacity (apparent Bmax = 971 fmol mg-1 of protein). The presence of 100 microM GTP in the incubation mixture did not modify [3H]-SCH 58261 binding parameters. 3. Competition experiments showed that [3H]-SCH 58261 binding is consistent with the labelling of A2A striatal Receptors. Adenosine Receptor agonists competed with the binding of 0.2 nM [3H]-SCH 58261 with the following order of potency: 2-hexynyl-5'-N-ethyl carboxamidoAdenosine (2HE-NECA) > 5'-N-ethylcarboxamidoAdenosine (NECA) > 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne (CGS 21680) > 2-phenylaminoAdenosine (CV 1808) > R-N6-phenylisopropylAdenosine (R-PIA) > N6-cyclohexylAdenosine (CHA) = 2-chloro-N6-cyclopentylAdenosine (CCPA) > S-N6-phenylisopropylAdenosine (S-PIA). 4. Adenosine Antagonists inhibited [3H]-SCH 58261 binding with the following order: 5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo[1,5-c] quinazoline (CGS 15943) > 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine (8FB-PTP) = SCH 58261 > xanthine amine congener (XAC) = (E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837S) > 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) > or = 8-phenyltheophylline (8-PT). 5. The Ki values for Adenosine Antagonists were similar to those labelled with the A2A agonist [3H]-CGS 21680. Affinities of agonists were generally lower. The A1-selective agonist, R-PIA, was found to be about 9 fold more potent than its stereoisomer, S-PIA, thus showing the stereoselectivity of [3H]-SCH 58261 binding. Except for 8-PT, the Adenosine agonists and Antagonists examined inhibited [3H]-SCH 58261 binding with Hill coefficients not significantly different from unity. 6. The present results indicate that [3H]-SCH 58261 is the first non-xanthine Adenosine Antagonist radioligand which directly labels A2A striatal Receptors. High Receptor affinity, good selectivity and very low non-specific binding make [3H]-SCH 58261 an excellent probe for studying the A2A Adenosine Receptor subtype in mammalian brain.

  • the non xanthine heterocyclic compound sch 58261 is a new potent and selective a2a Adenosine Receptor Antagonist
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: C Zocchi, Pier Giovanni Baraldi, Angela Monopoli, Ennio Ongini, A Conti, A Negretti, Silvio Dionisotti
    Abstract:

    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]-59-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 59-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.