Design, synthesis, and evaluation of analogues of 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide as orally available general anesthetics

Journal of Medicinal Chemistry
Indrani Choudhury-MukherjeeMilton L Brown

Abstract

We have recently discovered a novel class of compounds that have oral general anesthetic activity, potent anticonvulsant activity, and minimal hemodynamic effects. The 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide (1) demonstrated potent ability to reduce the minimum alveolar concentration (MAC) of isoflurane, with no effects on heart rate or blood pressure at therapeutic concentrations. Analogue 1 also had potent oral anticonvulsant activity against maximal electroshock (MES) and subcutaneous metrazol (scMET) models with a therapeutic index of 10 for MES activity. In this study, we further synthesized nine new racemic analogues and evaluated these compounds for effects on isoflurane MAC reduction and blood pressure. Preliminary data demonstrate potent reduction in the isoflurane MAC for two new compounds. Current mechanistic studies were unrevealing for effects on voltage-gated ion channels as a putative mechanism. Liposomal partitioning studies using (19)F NMR reveal that the aromatic region partitions into the core of the lipid. This partitioning correlated with general anesthetic activity of this class of compounds. Further, compound 1 was used at a concentration of 1 mM and slightly enhanced GABA(A) current in hippocampa...Continue Reading

References

May 1, 1992·Anesthesia and Analgesia·B DrengerT J Blanck
Sep 1, 1992·British Journal of Anaesthesia·C Frenkel, B W Urban
Apr 1, 1992·Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS·C Frenkel, B W Urban
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Sep 2, 2000·Anesthesiology·R DickinsonN P Franks

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Citations

Feb 26, 2004·Bioorganic & Medicinal Chemistry·Hilary A SchenckMilton L Brown
May 12, 2011·Chemical Communications : Chem Comm·Cheng-Pan ZhangJi-Chang Xiao
Jan 12, 2010·Chemistry : a European Journal·Niculina D BogdanDaniel P Funeriu
Nov 9, 2006·The Journal of Pharmacology and Experimental Therapeutics·Paulianda J JonesManoj K Patel
May 11, 2020·Central Nervous System Agents in Medicinal Chemistry·Arcadius V Krivoshein
Aug 9, 2008·Organic Letters·Kimberly Yearick, Christian Wolf

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