DEVELOPMENT OF DRUGS ACTING AT ADENOSINE RECEPTORS

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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 an don the possibility of therapeutics for treating neurodegenerative diseases. Chronic treatment with an adenosine agonist improves spaital 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 some adaptation (sensitization by antagonists/desensitization by agonists) of the mechanism of receptor activation, ether at the level 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 receptors 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with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.