Non-xanthine Adenosine Receptor Antagonist Research Articles

The effect of non-xanthine adenosine receptor antagonist on ventricular remodeling and RAAS in chronic heart failure

Objective To analyze the effect of non-xanthine adenosine receptor antagonist(SLV320) on the ventricular remodeling and renin-angiotensin-aldosterone system(RAAS)in animal experimental models of chronic heart failure(CHF). Methods The 40 healthy male New Zealand rabbits were received adriamycin by intravenous injection to establishing the experimental animal models and were randomly divided into 4 groups, which were high-dosage group(injected with SLV320,10.0μg·kg-1·d-1),medium-dosage group(injected with SLV320,5.0μg·kg-1·d-1),low-dosage group(injected with SLV320,2.5μg·kg-1· d-1)and furosemide group(fed with furosemide,2.0mg·kg-1·d-1).Each group had 10 rabbits and continuous treated for one week. The indexes of plasma renin activity(PRA),angiotensinⅡ(AngⅡ),aldosterone (ALD)and beta ntriuretic peptide(BNP)were detected at pre-and post-treatment,and compared among 4 groups. The indexes of left ventricular end-systolic dimension(LVESD), left ventricular end-diastolic dimension(LVEDD),left ventricular posterior wall(LVPW),left ventricle ejection fraction(LVEF),left ventricular fractional shortening(LVFS)and E/A at pre-and post-treatment were detected by echocardiography and compared among 4 groups. The wet weigh of the left and right ventricle were weigh accurately. And the indexes of left ventricle weight index(LVWI)and the body weight index(BWI)were calculated and compared among 4 groups. Results The plasma levels of PRA, Ang Ⅱ,ALD and BNP were no different among 4 groups before study(all P>0.05). The sequence of 4 groups on the plasma levels of RAASindexes was highdosage group 0.05). The sequence of 4 groups on the levels of LVEF and LVFS was high-dosage group>medium-dosage group>low-dosage group>furosemide group, and the sequences of LVESD,LVEDD,LVPW and E/A were high-dosage group<medium-dosage group<low -dosage group<furosemide group(all P<0.05). The sequences of 4 groups on the LVWI and RVWI were high-dosage group<medium-dosage group<low-dosage group<furosemide group(all P<0.05). Conclusion SLV320 can regulate the ventricular remodeling and RAAS in animal model of CHF and this effect was dose dependent. Key words: Non-xanthine adenosine receptor antagonist; Heart failure; Ventricular remodeling; Renin-angiotensin-aldosterone system

The role of adenosine A1 and A2A receptors in the caffeine effect on MDMA-induced DA and 5-HT release in the mouse striatum.

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) popular as a designer drug is often used with caffeine to gain a stronger stimulant effect. MDMA induces 5-HT and DA release by interaction with monoamine transporters. Co-administration of caffeine and MDMA may aggravate MDMA-induced toxic effects on DA and 5-HT terminals. In the present study, we determined whether caffeine influences DA and 5-HT release induced by MDMA. We also tried to find out if adenosine A1 and A2A receptors play a role in the effect of caffeine by investigating the effect of the selective adenosine A1 and A2A receptor antagonists, DPCPX and KW 6002 on DA and 5-HT release induced by MDMA. Mice were treated with caffeine (10 mg/kg) and MDMA (20 or 40 mg/kg) alone or in combination. DA and 5-HT release in the mouse striatum was measured using in vivo microdialysis. Caffeine exacerbated the effect of MDMA on DA and 5-HT release. DPCPX or KW 6002 co-administered with MDMA had similar influence as caffeine, but KW 6002 was more potent than caffeine or DPCPX. To exclude the contribution of MAO inhibition by caffeine in the caffeine effect on MDMA-induced increase in DA and 5-HT, we also tested the effect of the nonxanthine adenosine receptor antagonist CGS 15943A lacking properties of MAO activity modification. Our findings indicate that adenosine A1 and A2A receptor blockade may account for the caffeine-induced exacerbation of the MDMA effect on DA and 5-HT release and may aggravate MDMA toxicity.

Vasodilatory effect of pentoxifylline in isolated equine digital veins

The direct vasodilatory action of pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine) and its signalling pathway was evaluated in equine digital veins. Cumulative concentration-response curves to pentoxifylline (1 nM to 300 μM) were recorded in phenylephrine-precontracted equine digital vein rings under different experimental conditions. Relaxation to pentoxifylline was partially inhibited by endothelium removal, but was unaltered by CGS-15943 (a non-xanthine adenosine receptor antagonist; 3 μM). Nitric oxide synthase (NOS), soluble guanylate cyclase and cyclooxygenase (COX) inhibitors (Nω-nitro-L-arginine methyl ester (100 μM), ODQ (30 μM) and indomethacin (10 μM), respectively) significantly reduced the maximum relaxation induced by pentoxifylline. Moreover, pentoxifylline-induced relaxation was strongly reduced by Rp-8-Br-PET-cyclic guanosine monophosphate-S (a protein kinase G inhibitor; 3 μM), but remained unaffected by H-89 (a protein kinase A inhibitor; 2 μM). Pentoxifylline-induced relaxation was associated with a 3.4-fold increase in tissue cGMP content. To investigate whether pentoxifylline can affect cAMP- and cGMP-mediated relaxations, curves to forskolin, to sodium nitroprusside (SNP) and 8-bromo-cGMP were also recorded in endothelium-denuded equine digital vein rings pretreated with pentoxifylline (10 and 100 μM). Pentoxifylline only potentiated the SNP-mediated relaxation at the highest concentration (100 μM). Thus, pentoxifylline relaxed equine digital veins via endothelium-dependent and endothelium-independent components. The effect was mediated through both the NOS and COX pathways and could also result from inhibition of cGMP specific-phosphodiesterase activity at the highest concentrations used.

Regioselective One‐Pot Synthesis of 9‐Alkyl‐6‐chloropyrido[3,2‐e][1,2,4]triazolo[4,3‐a]pyrazines. Reactivity of Aliphatic and Aromatic Hydrazides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regioselective One-Pot Synthesis of 9-Alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines. Reactivity of Aliphatic and Aromatic Hydrazides

[reaction: see text] The one-pot synthesis of new 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines has been achieved. Hydrazides regioselectively reacted as nucleophiles with the 3-chloro substituent of 2,3-dichloropyrido[2,3-b]pyrazine. An intramolecular cyclization afforded the tricycle nonxanthine adenosine receptor antagonists.

9-Ethyladenine derivatives as adenosine receptor antagonists: 2- and 8-substitution results in distinct selectivities.

9-Ethyladenine was used as the basis for a series of non-xanthine adenosine receptor antagonists at human adenosine receptors. The adenine-based compounds were substituted in 2- or 8-position with a variety of side chains including some aryl or arylalkynyl groups previously tested as 2-substituents in adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) for their effect on agonist affinity. The affinity of the novel compounds was tested in radioligand binding assays (A1, A2A and A3) and inhibition of NECA-stimulated adenylyl cyclase activity (A2B) in membranes prepared from CHO cells stably transfected with the respective human receptor subtype. High affinity antagonists were identified for A1 (9-ethyl-8-phenyl-9H-adenine, compound 2; 6-(1-butylamino)-9-ethyl-8-phenyl-9H-purine, compound 3), A2A (8-ethoxy-9-ethyladenine; compound 8) and A3 (9-ethyl-8-phenylethynyl-9H-adenine, compound 5) with selectivities versus other receptor subtypes in the range of 10 to 600. These results demonstrate that adenine is a useful template for further development of high-affinity antagonists with distinct receptor selectivity profiles.

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A2a selective adenosine receptor antagonist

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. At 10 microM it displayed only minor inhibition of the bradycardic effects in guinea-pig atria to some concentrations of carbachol. At 10 microM, ZM 241385 had a small inhibitory effect on relaxant effects of isoprenaline in guinea-pig aortae but no effect on sodium nitrite-induced relaxation. ZM 241385(100 microM) was without effect on phenylephrine-induced tone in guinea-pig aortae.7. ZM 241385 (10 microM) had no inhibitory effect on rat hepatocyte phosphodiesterase types I, II, III and IV but caused a small inhibition of the calcium calmodulin-activated type I enzyme.8. ZM 241385 is the most selective adenosine A2a receptor antagonist yet described and is therefore a useful tool for characterization of responses mediated by A2 adenosine receptors.

A novel non-xanthine adenosine A 1 receptor antagonist

FK453, (+)-( R)-[( E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-2-piperidine ethanol, was examined for adenosine receptor antagonistic activity using isolated guinea-pig atria and aorta and for affinity for adenosine receptors in the rat cerebral cortex and striatum in comparison with FR113452 ( S enantiomer of FK453), PD116948 (1,3-dipropyl-8-cyclopentylxanthine), theophylline (1,3-dimethylxanthine) and CGS15943 ([1,2,4]triazolo[1,5- c]quinazolone). FK453 showed potent inhibition of the negative inotropic activity elicited by 10 μM adenosine with an IC 50 of 560 pM in guinea-pig atria. However, FK453 was less potent in inhibiting the relaxation induced by 3.2 μM adenosine and had an IC 50 of 1.18 μM in guinea-pig aorta. The IC 50 values for FR113452, PD116948, theophylline and CGS15943 were 1.18 μM, 1.31 nM, 20.2 μM and 74.2 nM in atria and > 100 μM, 656 nM, 239 μM, 127 nM in aorta respectively. In the binding study, FK453 antagonized [ 3H] N 6-cyclohexyladenosine binding to the rat cortical adenosine A 1 receptor with an IC 50 of 17.2 nM. The IC 50 values for FR113452, PD116948, theophylline and CGS15943 were 10.1 μM, 4.7 nM, 67.7 μM and 241 nM respectively. FK453 inhibited [ 3H]5′- N-ethylcarboxamideadenosine binding to rat striatum adenosine A 2 receptor with an IC 50 of 11.3 μM. FK453 had no adenosine A 1 receptor agonistic activity, since it had no negative inotropic activity up to 100 μM in isolated guinea-pig atria. These results demonstrate that FK453 is a novel non-xanthine adenosine receptor antagonist and is potent and selective for the adenosine A 1 receptor subtype.

Characterization of the Binding of a Novel Non-Xanthine Adenosine Antagonist Radioligand, [3H]CGS 15943, to Multiple Affinity States of the Adenosine A1Receptor in the Rat Cortex

Abstract The use of xanthine adenosine receptor antagonists such as 1,3-dipropyl-8-phenylxanthine (DPX) as radioligands for the characterization of adenosine receptor Pharmacology have been limited by their high lipophilicity, low specific activity, and their general lack of selectivity and affinity for adenosine receptors. Recent attempts to address the technical problems associated with this class of compounds has resulted in the development of several xanthine derivatives (e.g. the functionalized xanthine congeners [3H]XCC and [3H]XAC2, and [3H]CPX3) which bind with high and selective affinity to the adenosine A1 receptor subtype. Based on efforts to optimize non-xanthine adenosine receptor antagonists, CGS 15943, a derivative of the pyrazoloquinazoline benzodiazepine receptor inverse agonist CGS 82165, represents the first reported non-xanthine structure that potently blocks adenosine receptors6. CGS 15943 has nanomolar affinity for both A1 and A2 receptor subtypes6. However, in contrast to many of th...

Molecular Modelling of the Antagonist Binding Site on the Adenosine A, Receptor

Abstract With the aid of molecular modelling both adenosine and adenosine A, receptor antagonists belonging to various chemical classes were compared. A model for the antagonist binding site was developed. As a consequence 1H-imidazo[4, 5-c]-quinolin-4-amines were synthesized, constituting a novel class of potent non-xanthine adenosine receptor antagonists.