A1 Adenosine Receptor Agonists: Medicinal Chemistry and Therapeutic Potential

Abstract

Adenosine receptors are widely distributed in the body and modulate numerous physiological processes. Four receptor subtypes (termed A(1), A(2A), A(2B) and A(3)) have been identified based on their pharmacological profile and cloning. Activation of the A(1) adenosine receptors produces a number of effects including a reduction in heart rate and atrial contractility, the attenuation of the stimulatory actions of catecholamines on the heart as well as a reduction of lipolysis in adipose tissue. As a result, A(1)AR agonists have been targeted as anti-arrhythmic and cardioprotective agents. This review discusses the synthesis, structure-activity relationships and therapeutic potential of A(1)AR agonists.

Molecular dissection of G protein preference using Gsα chimeras reveals novel ligand signaling of GPCRs

“…AA1R is widely distributed in the body and modulates many physiological functions, including a decrease in heart rate and atrial contractility (17), the control of neurotransmission (34), and the regulation of hepatic glycogen metabolism, as well as a reduction of lipolysis in adipose tissue (10,12). AA1R has been reported to show higher intrinsic activity on activation of G i1 , G i2 , and G i3 than of G o , This study indicates that G icoupled pathways may be activated selectively by AA1R (22,28), consistent with our results shown in cells cotransfected with AA1R and Gsi /t/g , G si3 , or G so chimeras.…”

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…There are several pathological conditions in which the purinergic component of cotransmission is increased (Burnstock, 2002b). The emphasis in this article is on the pathophysiology and therapeutic potential of P2 receptors (see also Burnstock and Williams, 2000;Boeynaems et al, 2001;Yerxa, 2001;Burnstock, 2002a;Jacobson et al, 2002;Ralevic and Burnstock, 2003) and readers are referred to recent reviews about the therapeutic potential of P1 receptors (Fredholm et al, 2002(Fredholm et al, , 2005Okusa, 2002;Pelleg et al, 2002;Dhalla et al, 2003;Ribeiro et al, 2003;Hutchinson and Scammells, 2004;McCallion et al, 2004).…”

Adenosine and TNF-α exert similar inotropic effect on heart cultures, suggesting a cardioprotective mechanism against hypoxia

“…Whereas A 1 and A 3 receptors are negatively coupled to adenylyl cyclase, A 2 subtypes are positively coupled to adenylyl cyclase Mangoni and BarrereLemaire, 2004;Hutchinson and Scammells, 2004). Stress conditions such as hypoxia or ischemia induce break-down of ATP, followed by elevation of extracellular adenosine.…”

“…Both agonists decrease myocardial contractility via their negative inotropic effect, and decrease cAMP levels in the heart (Meldrum, 1998;Mubagwa and Flameng, 2001;Hutchinson and Scammells, 2004). Adenosine (Neumann et al, 2003) and TNF-α (Krown et al, 1995) inhibit, via their negative inotropic effect, calcium transients, that represent transition from the resting state to contractions.…”