Synthesis and antinociceptive effects of endomorphin-1 analogs with C-terminal linked by oligoarginine.
Endomorphins (EMs) cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit antinociception when given systemically because they are severely restricted by the blood-brain barrier (BBB). In the present study, we investigated herein a series of EM-1 analogs with C-terminal linked by oligoarginine in order to improve the brain delivery and antinociception after systemic administration. Indeed, all these analogs decreased the opioid receptor affinity and in vitro pharmacological activity. Moreover, analogs 4, 7-9 produced a less potent antinociceptive activity after intracerebroventricular (i.c.v.) administration, with the ED(50) values about 11- to 13-fold lower potencies than that of EM-1. Nevertheless, our results revealed that EM-1 failed to induce any significant antinociception at a dose of 50μmol/kg after subcutaneous (s.c.) administration, whereas equimolar dose of these four analogs produced a little low but significant antinociceptive effects. Naloxone (10nmol/kg, i.c.v.) significantly blocked the antinociceptive effects, indicating an opioid and central mechanism. These results demonstrated that C-terminal of EM-1 linked to oligoarginine improved the brain delivery, eliciting potent antinociception following peripheral administration.
Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, China.
Chang-lin
CL
Wang
Chao
C
Guo
Yi-qing
YQ
Wang
Ying
Y
Zhou
Qian
Q
Li
Jing-man
JM
Ni
Rui
R
Wang
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010146:Pain / Q000517:prevention & control*; D010147:Pain Measurement; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D014649:Vas Deferens / Q000187:drug effects
D000701:Analgesics, Opioid; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D009270:Naloxone; D001120:Arginine