title: Structure-activity relationships for ketamine esters as short-acting anaesthetics.
abstract: A series of aliphatic esters of the non-opioid anaesthetic/analgesic ketamine were prepared and their properties as shorter-acting analogues of ketamine itself were explored in an infused rat model, measuring the time after infusion to recover from both the anaesthetic (righting reflex) and analgesic (response to stimulus) effects. The potency of the esters as sedatives was not significantly related to chain length, but Me, Et and i-Pr esters were the more dose potent (up to twofold less than ketamine), whereas n-Pr esters were less potent (from 2- to 6-fold less than ketamine). For the Me, Et and i-Pr esters recovery from anaesthesia was 10-15-fold faster than from ketamine itself, and for the n-Pr esters it was 20-25-fold faster than from ketamine. A new dimethylamino ketamine derivative (homoketamine) had ketamine-like sedative effects but was slightly less potent than, but ester analogues of homoketamine had very weak sedative effects.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Jiney
authors.initials: J
authors.lastname: Jose
authors.forename: Swarna A
authors.initials: SA
authors.lastname: Gamage
authors.forename: Martyn G
authors.initials: MG
authors.lastname: Harvey
authors.forename: Logan J
authors.initials: LJ
authors.lastname: Voss
authors.forename: James W
authors.initials: JW
authors.lastname: Sleigh
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004952:Esters; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007649:Ketamine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D004952:Esters; D007649:Ketamine
keywords: Anaesthesia; DCM; Esters; Ketamine; LRR; N-methyl-d-aspartate; NMDA; PWR; Short-acting; Structure–activity relationship; dichloromethane; loss of righting reflex; pedal withdrawal reflex score