Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

Abstract

Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A 1 , A 2A , A 2B , and A 3 , of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A 1 AR of rat and mouse), CGS-21680 (for A 2A AR of rat), and Cl-IB-MECA (for A 3 AR of all three species). The functionally selective partial A 2B agonist BAY60-6583 was found to additionally bind to A 1 and A 3 AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A 1 ), preladenant (A 2A ), and PSB-603 (A 2B ) displayed high selectivity in all three investigated species. MRS-1523 acts as a selective A 3 AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies.

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

“…As shown in Figure 2a, the antiproliferative effect of adenosine was primarily mediated by A 2B AR, because it was abrogated by MRS. The opposing effects of the nonselective agonist NECA and the endogenous ligand adenosine are probably due to the higher affinity of NECA for the A 2A AR (see Supplementary Table S1) (Alnouri et al, 2015), thus explaining the previously reported divergences regarding the effect of AR activation on NHEK proliferation.…”

Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver

“…Notably, preischemic exposure to a selective A1R agonist (CCPA) essentially mimicked preconditioning in the liver through a mitochondrial adaptation similar to ischemic preconditioning. The single used dose of CCPA is expected to engage A1R since CCPA is 32 times selective for A1R versus A3 receptors in rats [61]. The possible involvement of A3 receptors in the effects of CCPA cannot be fully ruled out, although the role of A3 receptors in the preconditioning process is far from clear, with opposite effects in different tissues [62,63].…”

Purinergic drug targets for gastrointestinal disorders

“…Cl-ENBA (number 3 in Figure 2) is a more selective A 1 AR agonist for in vivo use than 1 and 2 (Carlin et al, 2017). CGS21680 (not shown) is an A 2A AR agonist in rat, but has substantial human (h) A 3 AR affinity (Alnouri et al, 2015). Potent A 2A AR agonist ATL-313 5 attenuates colitis in mice and reduces pro-inflammatory cytokines (Longhi et al, 2017).…”