Electrophilic derivatives of purines as irreversible inhibitors of A1 adenosine receptors

• Published in: Journal of medicinal chemistry 1989-05, Vol.32 (5), p.1043-1051
• Main Authors: Jacobson, Kenneth A, Barone, Suzanne, Kammula, Udai, Stiles, Gary L
• Format: Article
• Language: English
• Subjects: Adenosine - antagonists & inhibitors; Animals; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; In Vitro Techniques; Organic chemistry; Preparations and properties; Purines - chemical synthesis; Purines - pharmacology; Rats; Receptors, Purinergic - drug effects; Structure-Activity Relationship; Xanthine; Xanthines - chemical synthesis; Xanthines - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00125a019

Functionalized congeners derived from 1,3-dipropyl-8-phenylxanthine and from N6-phenyladenosine were derivatized to contain electrophilic groups (isothiocyanate, N-hydroxysuccinimide ester, maleimide, sulfonyl chloride, or alpha-haloacyl group) capable of reaction with nucleophiles on biopolymers. The goal was to inhibit chemically the A1 adenosine receptor by using reactive agonist and antagonist ligands. Some of the electrophilic derivatives were synthesized through acylation of amine-functionalized congeners using hetero- or homobifunctional reagents available for protein cross-linking. The affinity for A1 adenosine receptors was evaluated in competitive binding assays by using rat and bovine brain membranes. Several xanthine and adenosine thiourea derivatives prepared from 1,3- and 1,4-phenylene diisothiocyanate (DITC) were potent irreversible inhibitors of adenosine receptors. Derivatives of m-DITC, at concentrations between 10 and 500 nM, irreversibly eliminated binding at 90% of the A1-receptor sites. Receptor affinity of both xanthine and adenosine derivatives containing distal phenylthiourea substituents was diminished by electron-donating groups on the ring.