title: Structure-Based Optimization of Multifunctional Agonists for Opioid and Neuropeptide FF Receptors with Potent Nontolerance Forming Analgesic Activities.
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: 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.
authors: Zi-Long
authors: ZL
authors: Wang
authors: 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.
authors: Jia-Xin
authors: JX
authors: Pan
authors: 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.
authors: Jing-Jing
authors: JJ
authors: Song
authors: 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.
authors: Hong-Hai
authors: HH
authors: Tang
authors: 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.
authors: Hong-Ping
authors: HP
authors: Yu
authors: 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.
authors: Xu-Hui
authors: XH
authors: Li
authors: 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.
authors: Ning
authors: N
authors: Li
authors: 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.
authors: Ting
authors: T
authors: Zhang
authors: 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.
authors: Run
authors: R
authors: Zhang
authors: 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.
authors: Meng-Na
authors: MN
authors: Zhang
authors: 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.
authors: Biao
authors: B
authors: Xu
authors: 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.
authors: Quan
authors: Q
authors: Fang
authors: 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.
authors: Rui
authors: R
authors: Wang
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018013:Receptors, Neuropeptide / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D010455:Peptides; D018013:Receptors, Neuropeptide; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C083929:neuropeptide FF receptor