TY - JOUR
KW - Analgesics/chemical synthesis/chemistry/pharmacology
KW - Analgesics, Opioid/chemical synthesis/chemistry/pharmacology
KW - Animals
KW - Humans
KW - Molecular Docking Simulation
KW - Morphinans/chemical synthesis/chemistry/pharmacology
KW - Protein Structure, Quaternary
KW - Rats
KW - Receptors, Opioid, kappa/agonists
KW - Structure-Activity Relationship
KW - 4,5-epoxymorphinans
KW - binding structure
KW - nepenthones
KW - pharmacological heterogeneity
KW - kappa-opioid receptor
KW - mu-opioid receptor
AU - Wei Li
AU - Jian-Dong Long
AU - Yuan-Yuan Qian
AU - Yu Long
AU - Xue-Jun Xu
AU - Yu-Jun Wang
AU - Qing Shen
AU - Zuo-Neng Wang
AU - Xi-Cheng Yang
AU - Li Xiao
AU - Hong-Peng Sun
AU - Yu-Long Xu
AU - Yi-Yi Chen
AU - Qiong Xie
AU - Yong-Hui Wang
AU - Li-Ming Shao
AU - Jing-Gen Liu
AU - Zhui-Bai Qiu
AU - Wei Fu
A1 - 
AB - To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, kappa-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6alpha,14alpha-endo-ethenylthebaine and the 7alpha-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (Ki = 0.4 +/- 0.1 nM) and the highest selectivity (mu/kappa = 339, delta/kappa = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED50 = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED50 = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.
AD - Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Pharmacy, Dalian Medical University , Dalian 116044, China.; Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203, China.; Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.; Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , Shanghai 201203(TRUNCATED)
BT - ACS chemical neuroscience
C5 - Opioids & Substance Use
CP - 4
CY - United States
DO - 10.1021/acschemneuro.6b00321
IS - 4
JF - ACS chemical neuroscience
LA - eng
M1 - Journal Article
N2 - To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, kappa-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6alpha,14alpha-endo-ethenylthebaine and the 7alpha-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (Ki = 0.4 +/- 0.1 nM) and the highest selectivity (mu/kappa = 339, delta/kappa = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED50 = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED50 = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.
PP - United States
PY - 2017
SN - 1948-7193; 1948-7193
SP - 766
EP - 776
EP - 
T1 - The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities
T2 - ACS chemical neuroscience
TI - The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent kappa-Opioid Agonistic Activities
U1 - Opioids & Substance Use
U2 - 28033462
U3 - 10.1021/acschemneuro.6b00321
VL - 8
VO - 1948-7193; 1948-7193
Y1 - 2017
Y2 - Apr 19
ER -