Identification\nof Cytisine Derivatives as Agonists\nof the Human Delta Opioid Receptor by Supercomputer-Based Virtual\nDrug Screening and Transcriptomics

Delta opioid receptors\n(DORs) are rising as therapeutic\ntargets,\nnot only for the treatment of pain but also other neurological disorders\n(e.g., Parkinson’s disease). The advantage of DOR agonists\ncompared to μ-opioid receptor agonists is that they have fewer\nside effects and a lower potential to induce tolerance. However, although\nmultiple candidates have been tested in the past few decades, none\nhave been approved for clinical use. The current study focused on\nsearching for new DOR agonists by screening a chemical library containing\n40,000 natural and natural-derived products. The functional activity\nof the top molecules was evaluated in vitro through the cyclic adenosine\nmonophosphate accumulation assay. Compound <b>3</b> showed promising\nresults, and its activity was further investigated through transcriptomic\nmethods. Compound <b>3</b> inhibited the expression of <i>TNF</i>-α, prevented NF-κB translocation to the\nnucleus, and activated the G-protein-mediated ERK1/2 pathway. Additionally,\ncompound <b>3</b> is structurally different from known DOR agonists,\nmaking it a valuable candidate for further investigation for its anti-inflammatory\nand analgesic potential.