Functionalized congeners of 1,3-dialkylxanthines: preparation of analogs with high affinity for adenosine receptors

• Published in: Journal of medicinal chemistry Vol. 28; no. 9; pp. 1334 - 1340
• Main Authors: Jacobson, Kenneth A, Kirk, Kenneth L, Padgett, William L, Daly, John W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.09.1985
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Cerebral Cortex - metabolism; Chemical Phenomena; Chemistry; Esterification; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Organic chemistry; Preparations and properties; Rats; Receptors, Cell Surface - drug effects; Receptors, Cell Surface - metabolism; Receptors, Purinergic; Structure-Activity Relationship; Theophylline; Xanthenes - chemical synthesis; Xanthenes - pharmacology; Xanthines; Cyclization; Nitrogen heterocycle; Six membered ring; Bicyclic compound; Benzenic compound; Ureas; NMR spectrum; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00147a038

A series of functionalized congeners of 1,3-dialkylxanthines has been prepared as adenosine receptor antagonists. On the basis of the high potency of 8-(p-hydroxyphenyl)-1,3-dialkylxanthines, the parent compounds were 8-[4-[(carboxymethyl)oxy]phenyl] derivatives of theophylline and 1,3-dipropylxanthine. A series of analogues including esters of ethanol and N-hydroxysuccinimide, amides, a hydrazide, an acylurea, and anilides were prepared. The potency in blocking A1-adenosine receptors (inhibition of binding of N6-[3H]cyclohexyladenosine to brain membranes) and A2-adenosine receptors (inhibition of 2-chloroadenosine-elicited accumulations of cyclic AMP in brain slices) was markedly affected by structural changes distal to the primary pharmacophore (8-phenyl-1,3-dialkylxanthine). Potencies in the dipropyl series at the A1 receptor ranged from Ki values of 1.2 nM for a congener with a terminal amidoethyleneamine moiety to a Ki value of 58 nM for the parent carboxylic acid to a Ki of 96 nM for the bulky ureido congener. Certain congeners were up to 145-fold more active at A1 receptors than at A2 receptors. Various derivatives of the congeners should be useful as receptor probes and for radioiodination, avidin binding, and preparation of affinity columns.