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

Abstract

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.

Dissociative and analgesic properties of ketamine are independent and unaltered by sevoflurane general anesthesia

“…We conclude that ketamine-induced dissociation and analgesia are independent, suggesting that ketamine can be refined into a more targeted pain therapeutic. 8,11 We also conclude that ketamine may be used as a probe to advance our knowledge of dissociation independent pain circuits. We found that…”

“…We conclude that ketamine-induced dissociation and analgesia are independent, suggesting that ketamine can be refined into a more targeted pain therapeutic. 8,11 We also conclude that ketamine may be used as a probe to advance our knowledge of dissociation independent pain circuits. We found that dissociation did not entirely mediate the relation of analgesics to pain reduction although it may partly do so, and further replication of these effects would be desirable.…”

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…Independent from whether psychedelics will be approved as medicines, the knowledge generated is creating a unique opportunity for the development of novel, more efficacious designer drugs with structural analogy to psychedelic compounds (McLean et al, 2006;Zanos et al, 2017;Kenakin, 2019). Such a paradigm is already being explored for the design of a ketamine-and opioid-like analgesic with reduced side effects and could be employed in designing antidepressant and anxiolytic molecules with enhanced efficacy and reduced side effects (Manglik et al, 2016;Conibear and Kelly, 2019;Harvey et al, 2019). If skillfully harnessed, the knowledge generated could drastically improve our pharmacotherapeutic toolbox in psychiatry.…”

“…Ultimately, the knowledge generated by ongoing clinical studies may boost the acceptance of this approach by legislative, funding, and academic bodies, leading to the implementation of the necessary policy shifts to allow this therapy to reach the bedside. Lastly, compounds with structural analogy might represent an alternative to natural and semisynthetic psychedelics in an attempt to decouple the therapeutic from psychedelic effects of these compounds (McLean et al, 2006;Zanos et al, 2017;Harvey et al, 2019;Kenakin, 2019). For example, 2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]methyl)phenol, a novel and synthesized derivate of N-benzyl-substituted phenethylamine hallucinogens, displays strong binding affinity and selectivity for the 5HT 2A receptor (Hansen et al, 2014;Jensen et al, 2020).…”

Non-NMDA Mechanisms of Analgesia in Ketamine Analogs

“…Based on the R5 brain slice findings, we hypothesized that BaCl 2 would antagonize a central analgesic effect of R5. Rats were used for this investigation because previous behavioral investigations had utilized the rat model ( 5 , 6 , 8 , 26 ). The reason for this is the necessity for secure intravenous tail vein access for drug delivery, which limits drug metabolism by tissue esterases ( 27 ).…”