title: 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]-GTPγS 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.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhuang
authors.forename: Mei
authors.initials: M
authors.lastname: Yuan
authors.forename: Haoshan
authors.initials: H
authors.lastname: Wang
authors.forename: Weizhang
authors.initials: W
authors.lastname: Li
authors.forename: Ruibin
authors.initials: R
authors.lastname: Su
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D000818:Animals; D002082:Butylamines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D016466:CHO Cells; D003412:Cricetulus; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D015363:Quinolones / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000603834:4-butylamino-2-(3-fluorophenyl)(4, 3-c)quinolin-3-one; D058916:Adenosine A1 Receptor Antagonists; D002082:Butylamines; D015363:Quinolones