Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis.Using a molecular networking approach,five pairs of potent analgesic alkaloid enantiome...Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis.Using a molecular networking approach,five pairs of potent analgesic alkaloid enantiomers were isolated from the roots of Anacyclus pyrethrum(A.pyrethrum).Their structures were elucidated by comprehensive spectroscopic data analysis,including LR-HSQMBC and 1H–15N HMBC,quantum 13C NMR DP4+and ECD calculations,and single-crystal X-ray diffraction analysis.Anacyphrethines A(1)and B(2)are highly conjugated and polymethylated 6/6/6/6/5/7/5/5-fused octacyclic tetraazabic alkaloids possessing an unprecedented 8,14,18,24-tetraaza-octacyclo[16.8.2.11,23.04,28.05,17.09,16.011,15.021,27]nonacosane motif.Their biosynthetic pathways are proposed involving key aldol,hydroamination,and Schiff base reactions.All isolates showed potent analgesic effects in vivo.Even at a lower dose of 0.2 mg/kg,(±)-1 and(+)-1 still exhibited more potent analgesic activities than morphine.Interestingly,the racemic mixture(±)-1 showed stronger analgesic effect than either pure enantiomer alone at higher doses of 5 and 1 mg/kg;while,(±)-1 showed significant analgesic activities comparable to(+)-1 at lower doses of 0.2 and 0.04 mg/kg.(+)-1 had stronger analgesic effect than(−)-1 at five tested does.Further tests on 44 analgesic-related targets demonstrated that(+)-1 showed significant inhibitory effects against many ion channels such as TRPM8,Kv1.2,Kv1.3,and Cav2.1 with IC50 values of 1.10±0.26,4.20±0.07,2.20±0.24,and 10.40±0.69μmol/L,respectively,while(−)-1 primarily inhibited TRPC6,Kv1.2,and Kv1.3 ion channels with IC50 values of 0.81±0.05,0.91±0.04,and 1.50±0.13μmol/L,respectively,without affecting the opioid receptors,suggesting their non-opioid analgesic potentials.The molecular dockings provided structural guidance to develop potent non-opioid analgesics.展开更多
基金supported by the National Key R&D Program of China(2020YFE0205600)the Biological Resources Program,Chinese Academy of Sciences(KFJ-BRP-007-011,China)+2 种基金National Natural Science Foundation of China(22477034 and 22277034)Interdisciplinary Research Program of HUST(2023JCYJ037,China)International Cooperation Project of Hubei provincial key R&D plan(2023EHA040,China).
文摘Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis.Using a molecular networking approach,five pairs of potent analgesic alkaloid enantiomers were isolated from the roots of Anacyclus pyrethrum(A.pyrethrum).Their structures were elucidated by comprehensive spectroscopic data analysis,including LR-HSQMBC and 1H–15N HMBC,quantum 13C NMR DP4+and ECD calculations,and single-crystal X-ray diffraction analysis.Anacyphrethines A(1)and B(2)are highly conjugated and polymethylated 6/6/6/6/5/7/5/5-fused octacyclic tetraazabic alkaloids possessing an unprecedented 8,14,18,24-tetraaza-octacyclo[16.8.2.11,23.04,28.05,17.09,16.011,15.021,27]nonacosane motif.Their biosynthetic pathways are proposed involving key aldol,hydroamination,and Schiff base reactions.All isolates showed potent analgesic effects in vivo.Even at a lower dose of 0.2 mg/kg,(±)-1 and(+)-1 still exhibited more potent analgesic activities than morphine.Interestingly,the racemic mixture(±)-1 showed stronger analgesic effect than either pure enantiomer alone at higher doses of 5 and 1 mg/kg;while,(±)-1 showed significant analgesic activities comparable to(+)-1 at lower doses of 0.2 and 0.04 mg/kg.(+)-1 had stronger analgesic effect than(−)-1 at five tested does.Further tests on 44 analgesic-related targets demonstrated that(+)-1 showed significant inhibitory effects against many ion channels such as TRPM8,Kv1.2,Kv1.3,and Cav2.1 with IC50 values of 1.10±0.26,4.20±0.07,2.20±0.24,and 10.40±0.69μmol/L,respectively,while(−)-1 primarily inhibited TRPC6,Kv1.2,and Kv1.3 ion channels with IC50 values of 0.81±0.05,0.91±0.04,and 1.50±0.13μmol/L,respectively,without affecting the opioid receptors,suggesting their non-opioid analgesic potentials.The molecular dockings provided structural guidance to develop potent non-opioid analgesics.
