Design, synthesis, and evaluation of new endomorphin analogs with enhanced central antinociception after peripheral administration

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• 作者：Xin Liu ; Long Zhao ; Yuan Wang ; Lingyun Mou ; Junxian Yang ; Yixin Zhang ; Dan Wang ; Rui Wang ; ^{wangrui@lzu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BBB ; blood&ndash ; brain barrier ; Boc ; tert-butyloxycarbonyl ; cAMP ; cyclic adenosine monophosphate ; CNS ; central nervous system ; DAMGO ; H-Tyr-d-Ala-Gly-NMePhe-Gly-ol ; DCM ; dichloromethane ; DIEA ; N ; N-diisopropylethylamine ; DOR ; δ-opioid receptor ; DPDPE ; Tyr-c(d-Pen-Gly-Phe-d-Pen) ; ED50 ; median effective dose ; EDC ; N-ethyl-N-(3-(dimethylamino)propyl)-carbodiimide ; EM-1 ; endomorphin-1 ; EM-2 ; endomorphin-2 ; HEK293 ; human embryonic kidney ; HOBt ; 1-hydroxybenzotriazole ; i.c.v. ; intracerebroventricular
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：25
• 期：22
• 页码：5393-5397
• 全文大小：1004 K

文摘

We synthesized two novel endomorphin-1 (EM-1) analogs by substituting the C-terminus residue with (thienyl)-α-methylene-β-amino acids (Map). Several in vitro and in vivo assays were used to determine the activity of the analogs. The two EM-1 analogs showed subnanomolar binding affinity and functional activity at the μ-opioid receptor in HEK293 cells. Tail-flick and formalin tests further revealed that the EM-1 analogs were very effective after intravenous administration. Our results indicate that compared to endomorphin-1, the (thienyl)Map modified peptides showed improved blood–brain barrier permeability.