33900-28-6Relevant articles and documents
Pharmacodynamic and pharmacokinetic profiles of a neurotensin receptor type 2 (NTS2) analgesic macrocyclic analog
Chartier, Magali,Desgagné, Michael,Sousbie, Marc,Rumsby, Charles,Chevillard, Lucie,Théroux, Léa,Haroune, Lounès,C?té, Jér?me,Longpré, Jean-Michel,Boudreault, Pierre-Luc,Marsault, éric,Sarret, Philippe
, (2021/07/07)
The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8–13) analog. The Tyr11 residue of NT(8–13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 μg/kg) and tonic (ED50 = 7.1 μg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
Synthesis of 2-D-L-tryptophan by sequential Ir-catalyzed reactions
Vallakati, Ravikrishna,Plotnikov, Abel T.,Altman, Ryan A.
, p. 2261 - 2264 (2019/03/04)
Herein, we report a practical synthesis of 2-D-l-tryptophan via sequential Ir-catalyzed C–H borylation, and Ir-catalyzed C-2-deborylative deuteration steps. In this synthetic sequence, deprotection of the Boc and methyl ester groups proved challenging, due to replacement of deuterium with hydrogen. However, mild deprotection conditions were developed to avoid this D/H scrambling. Further, 2-D-L-Tryptophan is stable in many buffers used for biological studies.
Unlocking the potential of phenacyl protecting groups: CO2-based formation and photocatalytic release of caged amines
Speckmeier, Elisabeth,Klimkait, Michael,Zeitler, Kirsten
, p. 3738 - 3745 (2018/04/14)
Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.
