Allosteric Enhancers of A1 Adenosine Receptors: State of the Art and New Horizons for Drug Development

R.      Romagnoli; P.      G. Baraldi; M.      A. Tabrizi; S.      Gessi; P.      A. Borea; S.      Merighi

Abstract

Adenosine is an important autocoid, exerting its physiological effects on the human body by activation of four different G-protein- coupled-receptors (GPCRs) classified as A1, A2A, A2B, and A3. These receptors are coupled to secondary messenger systems including adenylate cyclase, inositol phosphate metabolism, and K+, KATP and Ca2+ channels. Pharmacological agents that increase the activation of A1 adenosine receptors in response to adenosine would be useful for treatment of cardiovascular, central nervous system, and inflammatory pathologies. Compounds that are able to enhance the activity of the A1-adenosine receptors by the endogenous ligand within specific tissues may have potential therapeutic advantages over non-endogenous agonists. Such an opportunity for intervention is provided by the concept of allosteric modulation of GPCRs. Therefore the use of allosteric enhancers to increase the responsiveness of the A1 receptors to endogenous adenosine at sites of its production is an appealing alternative to activation by exogenous agonists. This approach minimizes side effects because allosteric enhancers amplify the action of the agonist by stabilizing the agonist- A1-receptor– G protein ternary complex. The allosteric enhancement of the GABAA receptor by benzodiazepines is the most famous and successful example of this strategy. The aim of this article is to give an overview of the results obtained in this field and discuss the opportunities and challenges that this class of ligands might offer for medicinal chemistry and pharmacology.

Keywords: A1-adenosine receptor, allosteric modulators, enhancer, neuropatic pain, neuroprotection, Adenosine, G-protein-coupled-receptors (GPCRs), cyclase, inositol phosphate metabolism, K+, KATP, ionotropic receptor, butyric acid (GABA), orthosteric site, allosteric ligand, ATCM (allosteric ternary complex model, guanine nucleotides, bitopic, ligands, autacoid adenosine, G proteins, Gi/Go family, central nervous system (CNS), anticonvulsant, chronic obstructive pulmonary disease (COPD), adenosine mediates bronchoconstriction, inflammation, increased endothelial cell permeability, mucin production, ischemic preconditioning (IPC), protein kinase C, 2-amino-3-benzoylthiophene, cardiovascular tissues, antiarrythmic, structure-activity analysis, lipophilic substituents, antagonistic activities, neuropathic pain, placebo-controlled, multicenter, randomized, allosteric enhancer activity, naphthoyl ring, lipophilic chlorine, agonist, –, A1AR, G protein ternary complex, orthosteric antagonists, kinetic binding assay, K-score, orthosteric radioligand, α-subunit, Aminothiazole Derivatives, indenothiazole, antagonistic activity, therapeutic agent, COPD