NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids

详细信息    查看全文

• 作者：Nadja A. Simeth^a ; ^d ; Manuel Bause^a ; ^d ; Michael Dobmeier^a ; ^d ; Ralf C. Kling^b ; ^c ; Daniel Lachmann^a ; Harald H&uuml ; bner^b ; J&uuml ; rgen Einsiedel^b ; Peter Gmeiner^b ; ^{peter.gmeiner@fau.de} ; Burkhard Kö ; nig^a ; ^{burkhard.koenig@ur.de}
• 关键词：Neurotensin ; Peptides ; Non-natural amino acid
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：25
• 期：1
• 页码：350-359
• 全文大小：1394 K
• 卷排序：25

文摘

Stimulation of the NTS2 neurotensin receptor causes antipsychotic effects and leads to a promotion of the μ-opioid-independent antinociception, which is important in the modulation of tonic pain sensitivity. We report the synthesis and properties of a small library of peptidic agonists based on the active neurotensin fragment NT(8–13). Two tetrahydrofuran amino acid derivatives were synthesized to replace Tyr11 in NT(8–13). Additionally, Arg8, Arg9, and Ile12 of the lead peptide were exchanged by Lys, Lys, and Gly, respectively. The new compounds showed substantial NTS2 binding affinity and up to 1000-fold selectivity over NTS1. The highest selectivity (Ki(NTS2): 29 nM, Ki(NTS1): 35,000 nM) was observed for the peptide analog 17Rtrans.