Chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives: structure-activity relationships of potent, highly stereoselective A1-adenosine receptor antagonists.

A series of 33 novel, mostly chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives has been synthesized and investigated in radioligand binding assays at the high-affinity adenosine receptor (AR) subtypes A1 and A2a. The compounds can be envisaged as adenine and hypoxanthine analogs lacking the nitrogen in the 7-position (7-deazaadenines and 7-deazahypoxanthines). 7-Deazaadenines were much more potent than 7-deazahypoxanthines at AR with A1AR affinities in the low-nanomolar range, extraordinarily high selectivity for the rat brain A1AR versus the A2aAR (several thousandfold), and high stereoselectivity (up to 96-fold).

Tricyclic theophylline derivatives with high water-solubility: structure-activity relationships at adenosine receptors, phosphodiesterases, and benzodiazepine binding sites.

A series of tricyclic, highly water-soluble theophylline derivatives (pyrimido[2,1-f]-theophyllines) containing a basic side chain was investigated in rat brain A1- and A2 adenosine receptor binding assays, phosphodiesterase assays, and benzodiazepine binding studies. Among the new compounds adenosine receptor antagonists with affinities in the same range as the parent compound theophylline were identified. In addition, some compounds were selective for the A1 adenosine receptor subtype.

Amino-substituted 1,8-naphthyridines and pyrido[2,3-d]pyrimidines: new compounds with affinity for A1- and A2-adenosine receptors.

Two novel classes of adenosine receptor (AR) antagonists, 4-amino-1,8-naphthyridines and 5-aminopyrido[2,3-d]pyrimidines, have been identified and investigated in radioligand binding assays. The compounds exhibit affinities for A1 and A2a AR of rat brain in the micromolar range. 1,8-Naphthyridines are non-selective, or somewhat selective for either A1- or A2 AR.

Synthesis and structure-activity relationships of deazaxanthines: analogs of potent A1- and A2-adenosine receptor antagonists.

A set of 22 9-deazaxanthines (pyrrolo[3,2-d]pyrimidine-2,4-diones) and three 7-deazaxanthines (pyrrolo[2,3-d]pyrimidine-2,4-diones) with various substituents in the 1-, 3-, 7- or 9-, and 8-positions was synthesized and investigated in A1 and A2a adenosine receptor binding assays at rat brain cortical membranes and rat brain striatal membranes, respectively. 9-Deazaxanthines showed structure-activity relationships that were similar to those of xanthines. They were about equipotent to the corresponding xanthines at A2a adenosine receptors.