Ketamine esters and amides as short-acting anaesthetics: Structure-activity relationships for the side-chain

Dimitrov, Ivaylo; Harvey, Martyn; Voss, Logan J.; Sleigh, James W.; Bickerdike, M J; Denny, William A.

doi:10.1016/j.bmc.2019.02.010

Cited by 10 publications

(17 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whether such physiologic mechanisms hold relevance for developing more effective rapid-acting antidepressant treatments (i.e., intermittent administration paradigms) remains to be investigated. In this context, treatments such as nitrous oxide, short-acting ketamine analogs (Dimitrov et al, 2019), and theta burst stimulation may be particularly useful for several consecutive intermittent periods of administration in a single session (Fig. 4).…”

Section: Sleep and Rapid Antidepressant Effectsmentioning

confidence: 99%

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Rantamäki

Kohtala

2020

Pharmacol Rev

View full text Add to dashboard Cite

Brain and Mind Doctoral Program (S.K.), the Orion Research Foundation (S.K.), and the Emil Aaltonen foundation (S.K.). T.R. and S.K. are listed as coinventors on a patent application, wherein new tools enabling the development of rapid-acting antidepressants and the efficacy monitors thereof are disclosed based on the basic principles of ENCORE-D. T.R. and S.K. have assigned their patent rights to the University of Helsinki but will share a percentage of any royalties that may be received by the University of Helsinki.

show abstract

Section: Sleep and Rapid Antidepressant Effectsmentioning

confidence: 99%

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Rantamäki

Kohtala

2020

Pharmacol Rev

View full text Add to dashboard Cite

show abstract

“…Bolus and infusion regimens of KEA-1010 induced hypnosis characterised by sustained loss of righting reflex and blunted responses to external stimuli that appeared morphologically identical to that of ketamine. The requirement of higher infusion rates of KEA-1010 to maintain sedation, and rapid return of righting reflex following both bolus and infusion administration, reflects the ultra-rapid degradation by peripheral carboxylesterases (predominantly by the CES1 isoform) in keeping with the known pharmacokinetic profile of these compounds [24, 25, 27]. Modification of known drugs by addition of rapidly-degraded ester moieties has been previously employed to create a suite of ‘soft designer drugs’ (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…1 [2] which were developed to undergo tissue-based metabolism to inactive carboxylic acid by-products, have demonstrated rapid offset hypnosis in animal models [24–26]. Prior work in rodents has been undertaken to determine optimum side chain length and functional groups to maximise therapeutic sedative and antinociceptive actions of these novel agents [27]. Use of such analogues of ketamine has enabled titration of dose to hypnotic effect, while maintaining expeditious arousal following cessation of infusion in animal models [25].…”

Section: Introductionmentioning

confidence: 99%

KEA-1010, a ketamine ester analogue, retains analgesic and sedative potency but is devoid of Psychomimetic effects

Harvey

Sleigh

Voss

et al. 2019

BMC Pharmacol Toxicol

View full text Add to dashboard Cite

BackgroundKetamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents.MethodsKEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was further undertaken in morphine tolerant rats. Behavioural aberration was assessed following intravenous injection in rats undergoing TFL assessment and in auditory pre-pulse inhibition models.ResultsKEA-1010 demonstrated an ED50 similar to ketamine for loss of righting reflex following bolus intravenous injection (KEA-1010 11.4 mg/kg [95% CI 10.6 to 12.3]; ketamine (racemic) 9.6 mg/kg [95% CI 8.5–10.9]). Duration of hypnosis was four-fold shorter in KEA-1010 treated animals. KEA-1010 prolonged thermal tail flick responses comparably with ketamine when administered de novo, and augmented morphine-induced prolongation of tail flick when administered acutely. The analgesic effect of KEA-1010 on thermal tail flick was preserved in opioid tolerant rats. KEA-1010 resulted in increased paw-withdrawal thresholds in a rat paw incision model, similar in magnitude yet more persistent than that seen with fentanyl injection, and additive when co-administered with fentanyl. In contrast to ketamine, behavioural aberration following KEA-1010 injection was largely absent and no pre-pulse inhibition to acoustic startle was observed following KEA-1010 administration in rats.ConclusionsKEA-1010 provides antinociceptive efficacy in acute thermal and mechanical pain models that augments standard opioid analgesia and is preserved in opioid tolerant rodents. The NMDA channel affinity and psychomimetic signature of the parent compound ketamine is largely absent for KEA-1010.

show abstract

“…They minimise psychotomimetic side effects during recovery by undergoing very rapid metabolism by tissue esterases to the corresponding, much more polar, and inactive acids [10]. Ester side chains (CH2)2CO2 i Pr and (CH2)4CO2Me were particularly suitable [9,11]. We now extend these structure-activity studies to include analogues with Cl, Me, OMe, CF3 and OCF3 substituted at each available position on the benzene ring, together with the unsubstituted ring and 2-F variants (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters

et al. 2020

Self Cite

View full text Add to dashboard Cite

A series of benzene ring substituted ketamine N-alkyl esters were prepared from the corresponding substituted norketamines. Few of the latter have been reported since they have not been generally accessible via known routes. We report a new general route to many of these norketamines via the Neber (oxime to α-aminoketone) rearrangement of readily available substituted 2-phenycyclohexanones. We explored the use of the substituents Cl, Me, OMe, CF3, and OCF3, with a wide range of lipophilic and electronic properties, at all available benzene ring positions. The 2- and 3-substituted compounds were generally more active than 4-substituted compounds. The most generally acceptable substituent was Cl, while the powerful electron-withdrawing substituents CF3 and OCF3 provided fewer effective analogues.

show abstract

Ketamine esters and amides as short-acting anaesthetics: Structure-activity relationships for the side-chain

Cited by 10 publications

References 11 publications

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

KEA-1010, a ketamine ester analogue, retains analgesic and sedative potency but is devoid of Psychomimetic effects

Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters

Contact Info

Product

Resources

About