In vivo phenotypic validation of adenosine receptor-dependent activity of non-adenosine drugs

by Selleckchem | Mar 07 2023

Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four ARs (quadruple knockout, QKO). Alternatively, an adenosinergic effect was identified if a drug potentiated adenosine-induced hypothermia. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased the hypothermia caused by adenosine. Dipyridamole and nimodipine probably achieved this by inhibition of adenosine clearance via ENT1. Two drugs (cannabidiol, canrenoate) did not cause hypothermia in wild type mice. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia, but the hypothermia was unchanged in QKO mice indicating non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity; the hypoactivity was blunted in the QKO mice. Interestingly, the antidepressant amitriptyline caused hypothermia in wild type mice that was amplified in the QKO mice. Thus, we have identified adenosine-related effects for some drugs, while other candidates do not affect adenosine signaling by this in vivo assay. The adenosine-modulating drugs could be considered for repurposing based on predicted effects on AR activation.

Comments：

It appears that the researchers used mouse hypothermia as an in vivo screen for adenosinergic effects and identified several drugs that interact with adenosine receptors (ARs) in some way.

The study found that four drugs - dipyridamole, nimodipine, cilostazol, and cyclosporin A - increased the hypothermia caused by adenosine, which suggests that these drugs potentiate adenosine-induced effects. Dipyridamole and nimodipine are thought to achieve this by inhibiting adenosine clearance via ENT1.

Two other drugs - cannabidiol and canrenoate - did not cause hypothermia in wild-type mice, suggesting that they do not interact with adenosine signaling. Four more drugs - nifedipine, ranolazine, ketamine, and ethanol - caused hypothermia, but this effect was unchanged in mice lacking all four ARs, indicating that they act through non-adenosinergic mechanisms.

Zinc chloride caused hypothermia and hypoactivity, and the hypoactivity was blunted in mice lacking all four ARs, suggesting that the hypoactivity is mediated by adenosine signaling. Interestingly, the antidepressant amitriptyline caused hypothermia in wild-type mice that was amplified in mice lacking all four ARs, indicating an adenosinergic effect.

Overall, this study highlights the potential for repurposing some of these drugs based on their effects on AR activation. It also underscores the importance of considering the multiple mechanisms of action of drugs and the potential for off-target effects.