• Zi-Long Wang, Jia-Xin Pan, Jing-Jing Song, Hong-Hai Tang, Hong-Ping Yu, Xu-Hui Li, Ning Li, Ting Zhang, Run Zhang, Meng-Na Zhang, Biao Xu, Quan Fang, and Rui Wang.
• Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University , 199 Donggang West Road, Lanzhou, 730000, PR China.
• J. Med. Chem. 2016 Nov 23; 59 (22): 10198-10208.

AbstractThe opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent nontolerance forming analgesia. In this study, 11 analogues of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogues behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogues produced potent nontolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors. In addition, 11 also produced powerful analgesic effects in the formalin pain and CFA-induced chronic inflammatory pain models. Strikingly, following its repeated administration for 6 days, 11 did not produce antinociceptive tolerance in the tail-flick test and CFA-induced pain model. The present work indicates that it is reasonable to design multifunctional peptide ligands for opioid and NPFF receptors in a single molecule producing effective nontolerance forming antinociception.

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