Synthesis and antinociceptive effects of endomorphin-1 analogs with C-terminal linked by oligoarginine |
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Authors: | Wang Chang-lin Guo Chao Wang Yi-qing Zhou Ying Li Qian Ni Jing-man Wang Rui |
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Institution: | a Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China b Department of Life Sciences and Engineering, Bio-X Center, Academy of Fundamental and Interdisciplinary Sciences, Harbin Institute of Technology, Harbin 150001, China c School of Pharmacy, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China |
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Abstract: | 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 ED50 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 50 μmol/kg after subcutaneous (s.c.) administration, whereas equimolar dose of these four analogs produced a little low but significant antinociceptive effects. Naloxone (10 nmol/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. |
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Keywords: | Endomorphin-1 analogs BBB μ-Opioid receptor CPPs Oligoarginine Antinociception |
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