title: Design, synthesis, and evaluation of analogues of 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide as orally available general anesthetics.
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 hippocampal neurons at 10 microM. Altogether, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide exhibited excellent oral general anesthetic activity and appears devoid of significant side effects (i.e., alterations in blood pressure or heart rate).
authors.affiliation: Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville 22904, USA.
authors.forename: Indrani
authors.initials: I
authors.lastname: Choudhury-Mukherjee
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Schenck
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cechova
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Pajewski
authors.forename: Jaideep
authors.initials: J
authors.lastname: Kapur
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ellena
authors.forename: David S
authors.initials: DS
authors.lastname: Cafiso
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018681:Anesthetics, General / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D006339:Heart Rate / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000032:analysis; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D000577:Amides; D018681:Anesthetics, General; D000927:Anticonvulsants; D007473:Ion Channels; D008081:Liposomes; D011422:Propionates; D011963:Receptors, GABA-A; D007530:Isoflurane