DEVELOPMENT OF DRUGS ACTING AT ADENOSINE RECEPTORS

点击翻译按钮获取中文摘要

The extracellular adenosine receptor has a modulatory role in the nervous, circulatory, endocrine and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive. Recently this project has focused on the effects of adenosine agonists and antagonists in the central nervous system and on the possibility of therapeutics for treating neurodegenerative diseases. Chronic treatment with an adenosine agonist improves spatial memory retention and acquisition and indicates necessity of further studies directed towards Alzheimer's disease. Neuroprotective effects of acutely administered A1 receptor agonists and chronically administered A1 receptor antagonists have been demonstrated. Adenosine agonists prevent convulsions in several chemical and electrical seizure models and protect against excitotoxic neurodegeneration agonists and antagonists suggests same adaptation (sensitization by antagonists/desensitization by agonists) of the mechanism of receptor activation, either at the lefel of receptor or second messenger. An A3 agonist proved to be highly cerebroprotective in an ischemic model in gerbils. In summary, highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well. Since the three major subtypes of adenosine receptors have been cloned it has been possible to conduct molecular modeling of the receptor protein, based on sequence analyses and computerized energy minimizations. A hypothesis concerning the mode of binding to ligands to adenosine receptor has been derived. This hypothesis is consistent with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.