title: Novel endomorphin-1 analogs with C-terminal oligoarginine-conjugation display systemic antinociceptive activity with less gastrointestinal side effects.
abstract: In recent study, in order to improve the bioavailability of endomorphin-1 (EM-1), we designed and synthesized a series of novel EM-1 analogs by replacement of L-Pro(2) by β-Pro, D-Ala or Sar, together with C-terminal oligoarginine-conjugation. Our results indicated that the introduction of D-Ala and β-Pro in position 2, along with oligoarginine-conjugation, didn't significantly decrease the μ-affinity and in vitro bioactivity, and the enhancement of arginine residues did not markedly influence the μ-affinity of these analogs. All analogs displayed a significant enhancement of stability, which may be due to increased resistance to proline-specific enzymatic degradation. Moreover, following intracerebroventricular (i.c.v.) administration, analogs 1, 2, 4 and 5 produced significant antinociception and increased duration of action, with the ED50 values being about 1.8- to 4.2-fold less potent than that of EM-1. In addition, our results indicated that no significant antinociceptive activity of EM-1 was seen following subcutaneous (s.c.) injection, whereas analogs 1, 2, 4 and 5 with equimolar dose induced significant and prolonged antinociception by an opioid and central mechanism. Herein, we further examined the gastrointestinal transit and colonic propulsive latencies of EM-1 and its four analogs administered centrally and peripherally. I.c.v. administration of EM-1 and analogs 1, 2, 4 and 5 significantly delayed gastrointestinal transit and colonic bead propulsion in mice, but the inhibitory effects induced by these analogs were largely attenuated. It is noteworthy that no significant gastrointestinal side effects induced by these four analogs were observed after s.c. administration. Our results demonstrated that combined modifications of EM-1 with unnatural amino acid substitutions and oligoarginine-conjugation gave an efficient strategy to improve the analgesic profile of EM-1 analogs but with less gastrointestinal side effects when administered peripherally.
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: Yu-xiang
authors.initials: YX
authors.lastname: Diao
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: Yao
authors.initials: Y
authors.lastname: Zhang
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: D000700:Analgesics; D000818:Animals; D041981:Gastrointestinal Tract / Q000187:drug effects; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000700:Analgesics; D009842:Oligopeptides; C105293:endomorphin 1
keywords: Antinociception; Endomorphin-1 analogs; Gastrointestinal effect; Metabolic stability; Peripheral administration