Synthesis of 8-(cyclopentyloxy)phenyl substituted xanthine derivatives as adenosine A2A ligands

Abstract

The present paper describes the synthesis of a series of 8-(cyclopentyloxy)phenyl-xanthines and their evaluation for affinity for A1 and A2 adenosine receptors using radioligand binding assays. The effects of moving the cyclopentyloxy substituent with or without an ortho methoxy group on the various positions of the 8-phenyl ring have been studied. The vanilloid based xanthines 8-[4-(cyclopentyloxy)-3-methoxyphenyl]-1,3-dimethylxanthine (6a) (K(i)= 100 nM) and 8-[(4-cyclopentyloxy)-3-methoxyphenyl] -3-methyl-1-propylxanthine (12) (K(i) = 150 nM) displayed the highest affinity at A2A receptors as well as over 1000 fold selectivity over the A1 adenosine receptor subtype.

Xanthine scaffold: scope and potential in drug development

“…Xanthine provides maximum possibility of substitutions. Five types of mono substitutions (1-, 3-, 7-, 8- and 9-), eight di-substitutions (1,3-, 1,7-, 1,8-, 1,9-, 3,7-, 3,8-, 3,9- and 7,8-), three types of tri- substitutions (1,3,7-, 1,3,8-, 1,3,9-) [ 12 , 21 , 24 , 26 , 28 , 29 , 33 , 34 , 35 ]. Most of these substitutions are readily obtainable, but substitution at N 9 position becomes difficult because low nucleophilicity of N 9 position, electrophiles can only attack under special circumstances reference [29] .…”

Synthesis of a New Series of 1H‐Imidazol‐1‐yl Substituted 8‐Phenylxanthines as Adenosine Receptor Ligands

“…4) and 10% sucrose, and were diluted in assay buffer on thawing. The assays were performed using a similar method as described in [7] [14] [15]. Binding assays were performed using Milipore (Watford, UK) Multiscreen MHAF B3 H60 filter plates presoaked in 0.3% polyethyleneimine (PEI).…”

“…As a part of our ongoing research program directed towards the search for new 8-phenyl-substituted xanthine-based highly effective ligands for the adenosine receptors [6] [7], here we report a new series of 8-{[(imidazolyl)alkoxy]phenyl}xanthines along with variable substitutions at 1-, 3-, and 7-positions of the 8-phenylxanthine scaffold. The substitution pattern of the 8-phenyl substituent was also changed to study its effects on the affinity for adenosine A 1 and A 2A receptors.…”

“…Condensation of 5,6-diamino-1-methyluracil [7] [24] and 5,6-diamino-1-methyl-3-propyluracil [7] [24] with 2a in MeOH/AcOH 4 : 1 afforded the corresponding (benzylidene)amino derivatives 12a and 12b, which, on subsequent ring closure in refluxing SOCl 2 , gave the corresponding chloroalkoxy derivatives 13a and 13b (Scheme 3). Further, treatment with imidazole afforded (imidazolyl)propoxy derivatives 14a and 14b, respectively.…”

Bronchospasmolytic activity and adenosine receptor binding of some newer 1,3‐dipropyl‐8‐phenyl substituted xanthine derivatives

“…Xanthine provides maximum possible sites of substitutions. There are five sites for mono substitution [1‐, 3‐, 7‐, 8‐, and 9‐], for di‐substitutions there are eight sites [1,3‐, 1,7‐, 1,8‐, 1,9‐, 3,7‐, 3,8‐, 3,9‐ and 7, 8‐] and there are three sites for tri‐substitutions [1,3,7‐,1,3,8‐, 1,3,9‐] (Bansal et al, 2010; Miyamoto et al, 1993; Muller et al, 1998). The structure of xanthine gives extreme possibility for variation in derivatization because of the presence of N 1 , N 3 , N 7 , and C 8 positions for substitution.…”