Development Of Drugs Acting At Adenosine Receptors

Diabetes, Digestive, Kidney Diseases

Investigators

Linked publications & trials

Abstract

The extracellular adenosine receptors have a modulatory role in the nervous, circulatory, endocrine and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive. We have synthesized the first selective A3 adenosine receptor agonists and antagonists. We recently characterized the first allosteric modulators of this receptor. Imidazoquinoline and pyridinylisoquinoline derivatives were found to enhance the actions of agonists of the A3 receptor, and thus may prove to be suitable leads for the development of therapeutic agents based on this concept. Allosteric modulators of G-protein coupled receptors are a new approach to receptor activation without the limitations of use of directly-acting agonists as therapeutic agents. Adenosine A3 receptor agonists are of interest in protection of the heart and brain during ischemia. Also, the adenosine A3 agonist IB-MECA is currently in clinical trials for use in cancer treatment. Therefore agonist therapy at this receptor is of great interest. Adenosine A3 antagonists may be useful for the treatment of glaucoma. We are developing novel A3 antagonists based on nucleotide structures. We are currently studying systematically the structure activity relationships of adenosine derivatives that affect efficacy as A3 adenosine receptor agonists. Surprisingly, a commonly used A1-selective agonist, cyclopentyladenosine, was found to act as a pure antagonist at the A3 subtype. We are using mutagenesis to study the determinants of recognition of adenosine within the binding site of the A2A and A3 receptors, and proposing conformational factors involved in receptor activation. Since the four subtypes of adenosine receptors have been cloned it has been possible to conduct molecular modeling of the receptor protein, based on sequence analyses and homology modeling using the high resolution rhodopsin structure as template. We intend to use such a modeling approach for the design of more selective adenosine receptor agonists and antagonists. Receptor engineering has also been explored with the design and expression of constitutively active A3 receptors (continuously activated, in the absence of agonist) and the introduction of the concept of neoceptors. Neoceptors are tailor-made mutant receptors designed to respond only to synthetic agonist derivatives that do not activate the native receptor, We have utilized molecular modeling of the human A3 receptor to demonstrate the feasibility of the neoceptor approach using a novel electrostatic interaction within the binding site created by modifying both the receptor and ligand in concert. Recently this project has also focused on the effects of adenosine agonists and antagonists in the central nervous system and in the heart and on the possibility of therapeutics for treating neurodegenerative and cardiovascular diseases. An A3 agonist, administered chronically, proved to be highly cerebroprotective in an ischemic model in gerbils. A3 agonists cause morphological and biochemical changes in astroglial cells. Adenosine is released in large amounts during myocardial ischemia and is capable of activating both A1 or A3 receptors that occur on cardiac myocytes to exert a potent cardioprotective effect. We have shown that synthetic adenosine agonists, selective for either the A1 or A3 subtype, protect ischemic cardiac myocytes in culture and in the isolated perfused heart and thus might be beneficial to the survival of the ischemic heart. An acutely administered A3 agonist, Cl-IB-MECA, was cardioprotective in cell culture, through the selective activation of A3 receptors without side effects, such as bradycardia, associated with the A1 subtype. The protection was blocked in the presence of a selective A3 receptor antagonist. In summary, highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well. It is proposed that modulation of A2B and A3 receptors may be useful in treating asthma and inflammatory diseases. The pharmacolgical properties of novel xanthines developed in our lab that act as selective A2B receptor antagonists are being explored as potential antidiabetic and antiasthamtic agents. The first highly selective A2B receptor antagonist, synthesized in our section, has now been radiolabeled and is used in assaying newly synthesized analogues for affinity at the A2B receptor. We are also screening chemical libraries for novel leads for A2B receptor antagonists.