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Preclinical Research A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds. 8-(4-Cyclopentyloxy-5-methoxy-2-nitrophenyl)-1,3-dimethylxanthine (9e) proved to be a potent compound among the 2-nitrophenyl substituted xanthines exhibiting a Ki = 1 μM at human A2A ARs with at least 30 fold selectivity versus human A1 and A2B ARs. Replacement of 8-chloropropoxy phenyl with 8-nitrooxypropoxy phenyl resulted in a negligible change in binding affinity of the 8-substituted xanthines for various AR subtypes. Drug Dev Res 77 : 241-250, 2016. © 2016 Wiley Periodicals, Inc.

Preclinical Research A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds. 8-(4-Cyclopentyloxy-5-methoxy-2-nitrophenyl)-1,3-dimethylxanthine (9e) proved to be a potent compound among the 2-nitrophenyl substituted xanthines exhibiting a Ki = 1 μM at human A2A ARs with at least 30 fold selectivity versus human A1 and A2B ARs. Replacement of 8-chloropropoxy phenyl with 8-nitrooxypropoxy phenyl resulted in a negligible change in binding affinity of the 8-substituted xanthines for various AR subtypes. Drug Dev Res 77 : 241-250, 2016. © 2016 Wiley Periodicals, Inc.

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4-(10H)-ones (ATBIs) 1 and N-alkyl and N-acyl-(7-substituted-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amines (ITAs) 2, recently reported by us as two novel classes of selective A1 adenosine receptor (A1AR) antagonists using bovine cerebral membranes [Da Settimo et al., 2001, Novellino et al., 2002], were reevaluated for their affinity at human A1, A2A, and A3ARs expressed in CHO cells. All the ATBI derivatives 1 showed similar Ki values in the nanomolar range at both hA1AR and bA1AR, with a good selectivity for the hA1AR over the hA2AAR and hA3AR. The excellent correlation between Ki values at hA1AR and bA1AR in the ATBI series suggests that these compounds interact similarly at the binding sites of the two receptors. Unlike findings for the ATBIs 1, the Ki values of ITAs 2 at the hA1AR and bA1AR do not correlate very well. Several compounds (2g, 2i, 2j, 2m, 2n, and 2r) that bind with a nanomolar affinity to the bA1AR were found to be significantly less potent, or even inactive, at the hA1AR. A comparison of the amino acids in the TM regions involved in the recognition of the ligands at the bA1AR and hA1AR failed to provide a clear explanation of the great differences in ligand affinities between bA1AR and hA1AR. Some hypotheses are advanced to account for these differences. Drug Dev. Res. 63:1–7, 2004. © 2004 Wiley-Liss, Inc.

A series of novel pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine substituted at N 8 pyrazole nitrogen and at the 5-amino group was synthesized and their affinities to all four cloned human adenosine receptor subtypes were evaluated by competition binding assays using [ 3 H]-DPCPX (A 1 and A 2B ), [ 3 H]-SCH 58261 (A 2A ), and [ 3 H]-MRE3008-F20 (A 3 ) as radioligands. In particular, the structural requirements necessary for adenosine A 2B receptor recognition were investigated. These preliminary results confirm that the free amino group at the 5-position confers better A 2B affinity, while the effect of the chain at nitrogen pyrazole nucleus, the 8-position, seems to be preferred with respect to the corresponding N 7 regioisomers. The introduction of an aminoacyl chain at the 5-amino group produces better selectivity for A 2B receptors vs. A 2A , but the compounds still remain more potent for A 1 and a significant decrease (about 5-fold) of affinity at A 2B receptors was observed. Surprisingly, with these polar chains a good affinity at human A 3 adenosine receptors was also detected. The most interesting compounds in binding studies proved to be potent antagonists (nM range) in functional assays, measuring the inhibition of cAMP production induced by 100 nM NECA.

A 2A adenosine receptor (AR) antagonists are promising new drugs for the treatment of Parkinson's disease. Further potential therapeutic indications for A 2A AR antagonists include dementias, ischemias, and pain. Potent, selective A 2A AR antagonists have been developed, but their generally low water solubility is a major problem for conducting in vivo experiments. We developed a water-soluble phosphate prodrug (MSX-3) of a potent, selective A 2A AR antagonist (MSX-2), which is stable in aqueous solution, but rapidly cleaved in vivo by phosphatases to release the active compound MSX-2. Intracerebral application of MSX-3 led to a stimulation of motor activity in rats. Catalepsy, induced by pretreatment with either dopamine D1 or D2 antagonist, was potently reversed by intracerebral application of MSX-3. A new A 2A -selective antagonist radioligand, [ 3 H]MSX-2, was prepared, which exhibits a K D value of 8 nM at rat brain striatal membranes.