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

Journal of Medicinal Chemistry
Roberto FanelliF Cavelier

Abstract

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[8-13] 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.

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Citations

Feb 24, 2017·Journal of Chemical Information and Modeling·Bartholomé DelortNicolas Floquet
Apr 4, 2017·Journal of Medicinal Chemistry·Roberto FanelliFlorine Cavelier
Aug 3, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anna Lucia TorneselloFranco Maria Buonaguro
Jan 5, 2021·Expert Opinion on Therapeutic Patents·Malliga R Iyer, George Kunos
Jun 14, 2020·European Journal of Pharmacology·Pascal TétreaultPhilippe Sarret
Mar 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Rebecca L BrouillettePhilippe Sarret
Feb 20, 2021·Behavioural Brain Research·Mélanie VivancosPhilippe Sarret
Sep 6, 2020·Bioconjugate Chemistry·Roberto FanelliFlorine Cavelier
Sep 10, 2020·Journal of Medicinal Chemistry·Simon GonzalezSteven Ballet
May 7, 2021·Journal of Medicinal Chemistry·Samuel ObengChristopher R McCurdy
Jul 24, 2018·Journal of Medicinal Chemistry·Marc SousbieÉric Marsault
Oct 19, 2017·Journal of Medicinal Chemistry·Remya Ramesh, D Srinivasa Reddy
Mar 16, 2018·ACS Medicinal Chemistry Letters·Marc SousbieÉric Marsault
Jan 31, 2019·The Journal of Organic Chemistry·Raghunath ChowdhurySunil K Ghosh

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