Discovery of two novel branched peptidomimetics containing endomorphin-2 and RF9 pharmacophores: Synthesis and neuropharmacological evaluation. Issue 4 (15th February 2019)

• Record Type: Journal Article
• Authors: Zhang, Ting; Han, Zhenglan; Shi, Xuerui; Zhao, Weidong; Wang, Zilong; Zhang, Run; Xu, Biao; Zhang, Mengna; Zhang, Qinqin; Xiao, Jian; Zhu, Hanwen; Zheng, Ting; Fang, Quan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 4(2019)
• Page Start: 630
• Page End: 643
• Publication Date: 2019-02-15
• Subjects: ANOVA analysis of variance -- AUC area under the curve -- β-FNA beta-funaltrexamine -- BN-9 Tyr-D.Ala-Gly-Phe-Gln-Pro-Gln-Arg-Phe-NH2 -- Boc t-butyloxy carbonyl -- cAMP cyclic adenosine monophosphate -- CCK cholecystokinin -- DADLE Tyr-D.Ala-Gly-Phe-D.Leu-OH -- DCM dichloromethane -- deltorphin II Tyr-Ala-Phe-Glu-Val-Val-Gly-NH2 -- DIEA N, N′-diisopropylethylamine -- DMF dimethylformamide -- EC50 effective concentration 50% of maximum response -- ED50 effective dose 50% of maximum response -- EM-2 endomorphin-2 -- EN-9 Tyr-Pro-Phe-Phe-Gln-Pro-Gln-Arg-Phe-NH2 -- Fmoc 9-fluorenylmethoxycarbonyl -- HBTU 2-(1H-Benzotriazole-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate -- HOBt 1-hydroxybenzotriazole -- IBMX 3-isobutyl-1-methylxanthine -- i.c.v. intracerebroventricularly -- MBHA 4-methybenzhydrylamine -- % MPE the percent maximum possible effect -- nor-BNI nor-binaltorphimine -- NPFF neuropeptide FF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 -- NTI naltrindole -- PKA protein kinase A -- RF9 1-adamantanecarbonyl-RF-NH2 -- RP-HPLC reversed-phase high performance liquid chromatography -- S.E.M. standard error of the mean -- SR16435 1-(1-bicyclo[3.3.1]nonan-9-yl) piperidin-4-yl)indolin-2-one -- TFA trifluoroacetic acid; Branched peptidomimetics -- Endomorphin-2 -- RF9 -- Antinociception -- Tolerance -- Constipation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.01.003
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: EKR and RKE are mixed opioid agonists and NPFF1 antagonists/NPFF2 partial agonists. EKR and RKE exhibit the NPFF2 antagonism in cAMP test and neurite outgrowth assay. EKR and RKE produce supraspinal antinociception via the mu-opioid receptor. EKR and RKE exhibit NPFF2 agonistic activities in inflammatory pain model. EKR and RKE produce limited side effects on tolerance and constipation. Abstract: It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.