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Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities.
J Med Chem. 2016 11 23; 59(22):10198-10208.JM

Abstract

The 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.

Authors+Show Affiliations

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.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.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.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.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.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.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.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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27798836

Citation

Wang, Zi-Long, et al. "Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors With Potent Nontolerance Forming Analgesic Activities." Journal of Medicinal Chemistry, vol. 59, no. 22, 2016, pp. 10198-10208.
Wang ZL, Pan JX, Song JJ, et al. Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities. J Med Chem. 2016;59(22):10198-10208.
Wang, Z. L., Pan, J. X., Song, J. J., Tang, H. H., Yu, H. P., Li, X. H., Li, N., Zhang, T., Zhang, R., Zhang, M. N., Xu, B., Fang, Q., & Wang, R. (2016). Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities. Journal of Medicinal Chemistry, 59(22), 10198-10208.
Wang ZL, et al. Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors With Potent Nontolerance Forming Analgesic Activities. J Med Chem. 2016 11 23;59(22):10198-10208. PubMed PMID: 27798836.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities. AU - Wang,Zi-Long, AU - Pan,Jia-Xin, AU - Song,Jing-Jing, AU - Tang,Hong-Hai, AU - Yu,Hong-Ping, AU - Li,Xu-Hui, AU - Li,Ning, AU - Zhang,Ting, AU - Zhang,Run, AU - Zhang,Meng-Na, AU - Xu,Biao, AU - Fang,Quan, AU - Wang,Rui, Y1 - 2016/11/11/ PY - 2016/11/1/pubmed PY - 2017/6/14/medline PY - 2016/11/1/entrez SP - 10198 EP - 10208 JF - Journal of medicinal chemistry JO - J Med Chem VL - 59 IS - 22 N2 - The 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/27798836/Structure_Based_Optimization_of_Multifunctional_Agonists_for_Opioid_and_Neuropeptide_FF_Receptors_with_Potent_Nontolerance_Forming_Analgesic_Activities_ L2 - https://doi.org/10.1021/acs.jmedchem.6b01181 DB - PRIME DP - Unbound Medicine ER -