8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors

Abstract

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5nM, A2A: 230nM; Ki rat A1: 352nM, A2A: 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642nM, A2A: 203nM; Ki rat A1: 166nM, A2A: 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393nM, human A2A: 595nM, IC50 human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach.