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). Pyrimido[4,5-b]indoles were more potent A1AR antagonists compared to pyrrolo[2,3-d]pyrimidines. Compound 34a (APEPI) is one of the most potent and most selective nonxanthine A1AR antagonists known to date (Ki = 2.8 nM, > 2000-fold A1-selective). A new class of very potent A1AR antagonists has been identified, namely, 2-phenyl-7-deazaadenines bearing a substituent at the exocyclic amino group (N4-substituted pyrrolo[2,3-d]pyrimidines). (R)-N- (1-Phenylethyl)-4-amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin e (DPEAP, 17a) showed a Ki value of 6.7 nM at A1AR and > 4000-fold A1 selectivity. Different binding modes are postulated for the N4-substituted 4-aminopyrrolo[2,3-d]pyrimidines (e.g., 17a) and the 7-substituted derivatives (e.g., 1a), based on a comparison of steric, electronic, and hydrophobic properties of the two classes of compounds. Water solubility and lipophilicity have been determined for selected compounds. 4-Amino-5,6-dimethyl-2-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (4a) showed the highest water solubility/A1AR affinity ratio of 368 in the present series, over 2000-fold A1 selectivity, and 64-fold stereoselectivity (R > S). Therefore, 4a should be an interesting compound for in vivo evaluation.

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. 9-Deazaxanthines were generally at least 2-3-fold more potent than xanthines at A1 receptors and therefore exhibited higher A1 selectivities compared to the xanthines. 1,3-Dimethyl-8-(2-naphthyl)-9- deazaxanthine (19e) showed high affinity (Ki = 26 nM) and selectivity for A1 adenosine receptors. A hydroxyl function at N7 of 9-deazaxanthines was unfavorable for A1 and A2a receptor binding. 7-Deazaxanthines were considerably less potent compared to xanthines and to 9-deazaxanthines at both receptor subtypes.