Design, synthesis and evaluation of NTM-006-derived analgesics with enhanced potency

Based on the structure of NTM-006, a selective adenosine A₃ receptor (A₃AR) agonist developed by Janssen Pharmaceutica NV, a series of novel analgesics was designed and synthesized. Their analgesic activity was evaluated using the acetic acid-induced writhing model in mice. Among the 46 target compounds, 15 of them exhibited significant inhibition of writhing responses at 100 mg/kg (inhibition rate ≥ 32.89%), with analgesic efficacy comparable to that of the positive controls (NTM-006 and acetaminophen), indicating their potential for further development as analgesic agents. Dose-response studies revealed that compounds 37 and 40 inhibited writhing in a dose-dependent manner within the range of 30-300 mg/kg. Molecular docking further elucidated their potential binding modes with A₃AR, and molecular dynamics (MD) simulations revealed that compound 37 exhibited superior binding affinity and stability toward A₃AR compared to the lead compound NTM-006. The studies of preliminary structure-activity relationships and potential mechanisms of action provided insights for the design and development of novel analgesics targeting A₃AR.