Synthesis and Characterization in Vitro and in Vivo of (l)-(Trimethylsilyl)alanine Containing Neurotensin Analogues

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• 作者：Roberto Fanelli ; 脡lie Besserer-Offroy ; Adeline Ren茅 ; J茅r么me C么t茅 ; Pascal T茅treault ; Jasmin Collerette-Tremblay ; Jean-Michel Longpr茅 ; Richard Leduc ; Jean Martinez ; Philippe Sarret ; Florine Cavelier
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 8, 2015
• 年：2015
• 卷：58
• 期：19
• 页码：7785-7795
• 全文大小：488K
• ISSN：1520-4804

文摘

The silylated amino acid (l)-(trimethylsilyl)alanine (TMSAla) was incorporated at the C-terminal end of the minimal biologically active neurotensin (NT) fragment, leading to the synthesis of new hexapeptide NT[8鈥?3] analogues. Here, we assessed the ability of these new silylated NT compounds to bind to NTS1 and NTS2 receptors, promote regulation of multiple signaling pathways, induce inhibition of the ileal smooth muscle contractions, and affect distinct physiological variables, including blood pressure and pain sensation. Among the C-terminal modified analogues, compound 6 (JMV2007) carrying a TMSAla residue in position 13 exhibits a higher affinity toward NT receptors than the NT native peptide. We also found that compound 6 is effective in reversing carbachol-induced contraction in the isolated strip preparation assay and at inducing a drop in blood pressure. Finally, compound 6 produces potent analgesia in experimental models of acute and persistent pain.