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PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity.

ABSTRACT: Potent and selective adenosine A1 receptor (A1AR) antagonists with favourable pharmacokinetic properties used as novel diuretics and antihypertensives are desirable. Thus, we designed and synthesized a series of novel 4-alkylamino substitution-2-arylpyrazolo[4,3-c]quinolin-3-one derivatives. The aim of the present study is to characterize the biological profiles of the optimized compound, PQ-69. In vitro binding assay revealed a K i value of 0.96 nM for PQ-69 in cloned hA1 receptor, which was 217-fold more selective compared with hA2A receptors and >1,000-fold selectivity for hA1 over hA3 receptor. The results obtained from [(35)S]-GTP?S binding and cAMP concentration assays indicated that PQ-69 might be an A1AR antagonist with inverse agonist activity. In addition, PQ-69 displayed highly inhibitory activities on isolated guinea pig contraction (pA2 value of 8.99) induced by an A1AR agonist, 2-chloro-N6-cyclopentyl adenosine. Systemic administration of PQ-69 (0.03, 0.3, 3 mg/kg) increased urine flow and sodium excretion in normal rats. Furthermore, PQ-69 displayed better metabolic stability in vitro and longer terminal elimination half-life (t 1/2) in vivo compared with 1,3-dipropyl-8-cyclopentylxanthine. These findings suggest that PQ-69 exhibits potent antagonist effects on A1AR in vitro, ex vivo and in vivo, it might be a useful research tool for investigating A1AR function, and it could be developed as a potential therapeutic agent.

SUBMITTER: Lu M

PROVIDER: S-EPMC4272367 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity.

Lu Min M Wang Bo B Zhang Cheng C Zhuang Xiaomei X Yuan Mei M Wang Haoshan H Li Weizhang W Su Ruibin R Li Jin J

Purinergic signalling 20140924 4

Potent and selective adenosine A1 receptor (A1AR) antagonists with favourable pharmacokinetic properties used as novel diuretics and antihypertensives are desirable. Thus, we designed and synthesized a series of novel 4-alkylamino substitution-2-arylpyrazolo[4,3-c]quinolin-3-one derivatives. The aim of the present study is to characterize the biological profiles of the optimized compound, PQ-69. In vitro binding assay revealed a K i value of 0.96 nM for PQ-69 in cloned hA1 receptor, which was 21 ...[more]

PMID: 25248972

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Project description:Background and purposeAdenosine may be generated by hydrolysis of extracellular nucleotides by ectonucleotidases, including ectonucleoside triphosphate diphosphohydrolase 1 (CD39), ecto-5'-nucleotidase (CD73), nucleotide pyrophosphatase phosphodiesterase 1 (NPP-1) and tissue non-specific alkaline phosphatase (TNAP). Previous work from our laboratory has uncovered a critical role for adenosine A1 receptors (A1 R) in osteoclastogenesis; blockade or deletion of these receptors diminishes osteoclast differentiation. Interestingly, selective A1 R agonists neither affect basal osteoclastogenesis nor do they reverse A1 R antagonist-mediated inhibition of osteoclastogenesis. In this study, we determined whether ectonucleotidase-mediated adenosine production was required for A1 R antagonist-mediated inhibition, and, when we saw no effect, determined whether A1 R was constitutively activated and the antagonist was acting as an inverse agonist to diminish osteoclast differentiation.Experimental approachOsteoclast formation derived from wild-type, CD39 knockout (KO), CD73 KO, NPP-1 KO and TNAP KO mice was examined by tartrate-resistant acid phosphatase staining of receptor activator of NF-κB ligand-macrophage colony-stimulating factor-stimulated osteoclasts and osteoclast gene expression (Ctsk, Acp5, MMP-9 and NFATc1). Intracellular cAMP concentration was determined by elisa.Key resultsRolofylline inhibited osteoclast formation in a dose-dependent manner (IC50 = 20-70 nM) in mice lacking all four of these phosphatases, although baseline osteoclast formation was significantly less in precursors from CD73 KO mice. Rolofylline (1 μM) stimulates cAMP production in bone marrow macrophages by 10.23 ± 0.89-fold.Conclusions and implicationsBased on these findings, we hypothesize that the A1 R is constitutively activated in osteoclast precursors, thereby diminishing basal AC activity, and that A1 R antagonists act as inverse agonists to release A1 R-mediated inhibition of basal AC activity and permit osteoclast differentiation. The constitutive activity of A1 R promotes osteoclast formation and down-regulation of this activity blocks osteoclast formation.

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PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity.

Publications

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity.

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