title: Development of Rapidly Metabolized and Ultra-Short-Acting Ketamine Analogs.
abstract: BACKGROUND
  Ketamine is a well-established, rapidly acting dissociative anesthetic. Clinical use is limited by prolonged psychotomimetic phenomena on emergence, often requiring the coadministration of additional hypnotic drugs. We hypothesized that the development of ketamine ester analogs with ultrashort offset times might markedly reduce the dysphoric emergence phenomena and, hence, increase the utility of a ketamine-like hypnotic and analgesic. Here, we describe the results of studies that seek to define the pharmacology of 5 esters of ((1-(2-chlorophenyl)-2-oxocyclohexyl)amino)pentanoate hydrochloride, the first ketamine analogs designed to be susceptible to ultrarapid metabolism.
  
  
  METHODS
  Five norketamine ester analogs (R1-R5) were compared by ability to produce loss of righting and nociceptive blunting in rats. Toxicity testing was performed for 2 analogs (R1, R5) with 50% lethal dose (LD50) estimation in rats. In vitro metabolic stability was tested in rabbit plasma and whole blood by high-performance liquid chromatography. Behavioral and hemodynamic effects were observed in rabbits. We estimated the pharmacokinetics of these analogs in rabbits.
  
  
  RESULTS
  All 5 norketamine esters produced rapid loss of righting reflex and diminished pedal withdrawal with ultrarapid offset in the models studied (return of righting reflex 87 seconds [interquartile range (IQR) 78-131] R1 vs 996 seconds [IQR 840-1304] ketamine in rats; P < 0.01). The LD50 was comparable to that of ketamine (LD50 R1 50.2 mg/kg [95% confidence interval, 30-63]). For all analogs, hydrolysis to sole carboxylic acid derivatives was most rapid in vivo (clearance 1.61 L/kg/min R1 [IQR 0.40-2.42]), followed by whole blood and then plasma. Analog R5 demonstrated relatively greater nociceptive blunting than hypnotic effect (P < 0.001; pedal withdrawal score comparison with R1).
  
  
  CONCLUSIONS
  The 5 norketamine ester analogs retain the hypnotic characteristics of the parent compound, yet display rapid offset due to ultrarapid metabolism.
authors.affiliation: From the Waikato Clinical School, University of Auckland, Hamilton, New Zealand; and Auckland Cancer Society Research Center, School of Medical Sciences, Auckland, New Zealand.
authors.forename: Martyn
authors.initials: M
authors.lastname: Harvey
authors.forename: Jamie
authors.initials: J
authors.lastname: Sleigh
authors.forename: Logan
authors.initials: L
authors.lastname: Voss
authors.forename: Jiney
authors.initials: J
authors.lastname: Jose
authors.forename: Swarna
authors.initials: S
authors.lastname: Gamage
authors.forename: Frederik
authors.initials: F
authors.lastname: Pruijn
authors.forename: Sarath
authors.initials: S
authors.lastname: Liyanage
authors.forename: William
authors.initials: W
authors.lastname: Denny
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000639:trends*; D005260:Female; D006993:Hypnotics and Sedatives / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D007649:Ketamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D057897:Reflex, Righting / Q000187:drug effects / Q000502:physiology
chemical_list: D006993:Hypnotics and Sedatives; D007649:Ketamine; C033419:norketamine
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