Design of an equilibrative nucleoside transporter subtype 1 inhibitor for pain relief

Nicholas J. Wright, Yutaka Matsuoka, Hyeri Park, Wei He, Caroline G. Webster, Kenta Furutani, Justin G. Fedor, Aidan McGinnis, Yiquan Zhao, Ouyang Chen, Sangsu Bang, Ping Fan, Ivan Spasojevic, Jiyong Hong (), Ru-Rong Ji () and Seok-Yong Lee ()
Additional contact information
Nicholas J. Wright: Duke University School of Medicine
Yutaka Matsuoka: Duke University School of Medicine
Hyeri Park: Duke University
Wei He: Duke University School of Medicine
Caroline G. Webster: Duke University
Kenta Furutani: Duke University School of Medicine
Justin G. Fedor: Duke University School of Medicine
Aidan McGinnis: Duke University School of Medicine
Yiquan Zhao: Duke University
Ouyang Chen: Duke University School of Medicine
Sangsu Bang: Duke University School of Medicine
Ping Fan: Duke University School of Medicine
Ivan Spasojevic: Duke University School of Medicine
Jiyong Hong: Duke University
Ru-Rong Ji: Duke University School of Medicine
Seok-Yong Lee: Duke University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The current opioid crisis urgently calls for developing non-addictive pain medications. Progress has been slow, highlighting the need to uncover targets with unique mechanisms of action. Extracellular adenosine alleviates pain by activating the adenosine A1 receptor (A1R). However, efforts to develop A1R agonists have faced obstacles. The equilibrative nucleoside transporter subtype 1 (ENT1) plays a crucial role in regulating adenosine levels across cell membranes. We postulate that ENT1 inhibition may enhance extracellular adenosine levels, potentiating endogenous adenosine action at A1R and leading to analgesic effects. Here, we modify the ENT1 inhibitor dilazep based on its complex X-ray structure and show that this modified inhibitor reduces neuropathic and inflammatory pain in animal models while dilazep does not. Notably, our ENT1 inhibitor surpasses gabapentin in analgesic efficacy in a neuropathic pain model. Additionally, our inhibitor exhibits less cardiac side effect than dilazep via systemic administration and shows no side effects via local/intrathecal administration. ENT1 is colocalized with A1R in mouse and human dorsal root ganglia, and the analgesic effect of our inhibitor is linked to A1R. Our studies reveal ENT1 as a therapeutic target for analgesia, highlighting the promise of rationally designed ENT1 inhibitors for non-opioid pain medications.

Date: 2024
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DOI: 10.1038/s41467-024-54914-7

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