title: Endomorphin-2 analogs with C-terminal esterification produce potent systemic antinociception with reduced tolerance and gastrointestinal side effects.
abstract: C-terminal esterification of opioid peptides may change their opioid activities due to the modified physicochemical properties. In the present study, the pharmacological activities of C-terminal esterified endomorphin-2 (EM-2) analogs 1-3 were characterized by in vitro metabolic stability and octanol/buffer distribution assays. Also, the antinociceptive profiles in the radiant heat paw withdrawal test and related side effects of these analogs were determined. Our results showed that all three analogs significantly increased the metabolic stability and lipophilicity. Moreover, analogs 1-3 displayed potent antinociceptive activities after intracerebroventricular (i.c.v.) administration. Analogs 1 and 3 exhibited about 2-fold higher antinociception than EM-2, and differential opioid mechanisms were involved. In addition, EM-2 at 50 μmol/kg failed to produce any significant antinociceptive activity after subcutaneous (s.c.) administration, whereas equimolar dose of analogs 1-3 produced significant analgesic effects. Analog 3 showed the highest antinociceptive activity after systemic administration, which was consistent with its in vitro stability and lipophilicity. We further evaluated the antinociceptive tolerance of analogs 1-3. In acute tolerance test, analogs 1-3 shifted the dose-response curves rightward by only 1.4-3.2 fold as determined by tolerance ratio, whereas EM-2 by 5.6-fold, demonstrating reduced antinociceptive tolerance. Also, analogs 1 and 2 decreased chronic antinociceptive tolerance by central and peripheral administration of drugs. In particular, analogs 3 displayed insignificant chronic antinociceptive tolerance. Furthermore, analogs 1-3 were less prone to induce gastrointestinal side effects at analgesic doses. The present investigation gave the evidence that C-terminal esterified modifications of EM-2 will facilitate the development of novel opioid analgesics with reduced side effects.
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China. Electronic address: wangcl@hit.edu.cn.
authors.forename: Chang-Lin
authors.initials: CL
authors.lastname: Wang
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Qiu
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China.
authors.forename: Dai-Jun
authors.initials: DJ
authors.lastname: Yang
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China.
authors.forename: Bi-Yu
authors.initials: BY
authors.lastname: Yuan
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China.
authors.forename: Feng-Tong
authors.initials: FT
authors.lastname: Han
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002408:Catheters, Indwelling; D003106:Colon / Q000187:drug effects / Q000502:physiology; D004355:Drug Stability; D004361:Drug Tolerance; D004951:Esterification; D005772:Gastrointestinal Transit / Q000187:drug effects; D006358:Hot Temperature; D008297:Male; D051379:Mice; D015394:Molecular Structure; D059226:Nociceptive Pain / Q000188:drug therapy; D009842:Oligopeptides / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; C105294:endomorphin 2
keywords: Antinociception; C-terminal esterification; Endomorphin-2 analogs; Lipophilicity; Side effects