Adenosine receptor ligands: differences with acute versus chronic treatment

Abstract

Adenosine receptors have been the target of intense research with respect to potential use of selective ligands in a variety of therapeutic areas. Caffeine and theophylline are adenosine receptor antagonists, and over the past three decades a wide range of selective agonists and antagonists for adenosine receptor subtypes have been developed. A complication to the therapeutic use of adenosine receptor ligands is the observation that the effects of acute administration of a particular ligand can be diametrically opposite to the chronic effects of the same ligand. This 'effect inversion' is discussed here by Ken Jacobson and colleagues, and has been observed for effects on cognitive processes, seizures and ischaemic damage.

Fig. 1

Structures of a: agonists. and b: antagonists at adenosine receptors APEC, 2-[(2-aminoethylamino)carbonylethylphenylethylamino]-5′-N-ethylcarboxamidoadenosine; CPT, 8-cyclopentyltheophylline; CPX. 8-cyclopentyl-1,3-dipropylxanthine; CSC, 8-(3-chlorostyryl)caffeine; DPMA, N⁶-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine: IB-MECA, N⁶-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine; and XAC. 8-(4-[({[(2-aminoethyl)amino]carbonyl}methyl)oxy]phenyl}-1,3-dipropylxanthine.

Fig. 2

Effect of chronic administration of caffeine on the densities of several receptors and an ion channel in various brain regions. (■, cortex; □, cerebellum; and ■, striatum.) Caffeine was ingested in drinking water (1 g l⁻¹) for 4 days by male NIH Swiss mice. Binding assays were carried out four hours after cessation of caffeine administration via the drinking water. Values are calculated from data in Refs , , and expressed as percent of control levels. *p<0.05 significantly different from control values.