Synthesis of xanthines as adenosine antagonists, a practical quantitative structure-activity relationship application

Abstract

A set of 56 8-phenylxanthines, previously tested for adenosine antagonism (adenosine A1 receptor affinity), was analyzed by quantitative structure-activity relationship (QSAR) techniques. The resulting QSAR revealed that (1) the most potent receptor binders had already been made in this series and thus suggested the termination of synthesis of compounds with additional phenyl substituents to increase potency and (2) potency was much more strongly affected by changes in ortho than para phenyl substitution. On the basis of this study, an additional 20 compounds were synthesized that contained primarily para substituents designed to increase aqueous solubility. High potency was maintained among the resulting sulfonamide derivatives (as predicted by the QSAR), and aqueous solubility was dramatically increased. Furthermore, in vitro antagonism of an adenosine receptor mediated physiological effect was demonstrated.

Adenosine A1 receptors in mammalian brain: Species differences in their interactions with agonists and antagonists

“…A clearer evaluation of the contribution of the 8-phenyl substituent to the activity of xanthines among species can be made by comparing 8PT to theophylline. Guinea pig A1 receptors appear to be least sensitive to the loss of the phenyl ring (8PT/theophylline ratio = 7), whereas human, rat, mouse, cow, and rabbit have ratios of 44, 63, 166, 213, and 312, respectively. It is difficult to derive a meaningful structure-activity relationship based on five compounds, and this has been done elsewhere Daly et al, 1985;Hamilton et al, 1985;Schawbe et al, 19851. However, it is clear from the present data that A1 receptors in different species have different structural requirements for xanthine activity.…”

A New Series of 2-Alkoxy(aralkoxy)-[1,2,4]triazolo[1,5-a]quinazolin-5-ones as Adenosine Receptor Antagonists

“…7,8) The naturally occurring xanthines such as caffeine and theophylline were the initial prototypic AR antagonists. 9,10) The many attempts to improve their potency and selectivity have resulted in the preparation of a large number of xanthine derivatives, and much is known now in terms of their structure activity and structure selectivity relationships, as well as about their pharmacological activity. [11][12][13] However, most of these xanthine derivatives showed poor water solubility and a high metabolic rate (specially due to their interaction with cytochrome P450 family) which strongly limitate its drug ability profile.…”

“…[23][24][25][26][27][28][29][30][31][32][33] In our previous papers, [34][35][36] we have described the synthetic methodology to obtain a new series of 2-alkoxy-[1,2,4]triazolo[1,5-a]quinazolin-5-ones and their derivatives 1-11, Chart 1. In this scenario, and as a part of our interest in the search for novel adenosine receptor antagonists, we herein report the pharmacological characterization of our compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) at all adenosine receptor subtypes.…”

Search for new antagonist ligands for adenosine receptors from QSAR point of view. How close are we?

“…One of the first QSAR models in this regard was reported by Hamilton et al 96 in 1985. In this research the authors used a set of 56 xanthine derivatives ( Fig.…”