A1 adenosine receptor (A1AR) belongs to a subfamily of four G protein coupled cell surface receptors including A1, A2A, A2B and A3.  A1AR is expressed in the highest density in the brain and adipose tissue, kidney and atria and to a lower extent in ventricles, lung, pancreas, liver and GI tract.  A1AR and A3AR couple to inhibitory Gi/Go protein, which inhibits adenylate cyclase (AC) activity, thus reducing cellular cAMP levels.  On the other hand A2AAR and A2BAR couple to stimulatory Gs protein and stimulate AC activity.  Adenosine receptors can also modulate phospholipase C (PLC), influencing inositol triphosphate and Ca2+ release from internal stores.  In addition, ARs act on both potassium and calcium channels.  Many pathophysiological states are associated with changes in adenosine levels, inter alia, asthma, neurodegenerative disorders, psychosis, anxiety and chronic inflamatory disease. Thus, A1AR has been linked to a variety of possible drug targets.  Its presence in the brain has been linked to inhibition of synaptic transmission, and its presence in the atrioventicular node of the heart has resulted in clinical development of selective A1AR agonists to be used as antiarrythmic agents.  Although numerous A1AR agonists have already been developed, few are orally bioavailable.  Furthermore, clinical applications of the existing compounds have been greatly hampered by their cardiovascular side effects.  Herein we disclose a novel series of compounds possessing marked potency against A1AR shown in several orthogonal in vitro assays.  These A1AR agonists are orally bioavailable and highly efficacious in in vivo mouse models in a dose dependant manner.  Apparent lack of cardiovascular side effects makes this new series of compounds especially interesting from a therapeutic standpoint.

Novel, orally bioavaliable adenosine A<sub>1</sub> receptor agonists with antinociceptive effects in mice

243rd National Meeting (2012)

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Novel, orally bioavaliable adenosine A1 receptor agonists with antinociceptive effects in mice

Novel, orally bioavaliable adenosine A₁ receptor agonists with antinociceptive effects in mice