The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.
Bryan L Roth, Simon Gibbons, Warunya Arunotayanun, Xi-Ping Huang, Vincent Setola, Ric Treble, Les Iversen
PLoS ONE June 14, 2016 DOI: 10.1371/journal.pone.0059334 via DOAJ
Summary
AI-generated from the abstractNovel ketamine and phencyclidine analogues sold as designer drugs bind with high affinity to the same NMDA receptor site as the parent compounds, based on radioligand binding assays conducted through a national screening program. Methoxetamine and 3-MeO-PCE, along with the 3- and 4-methoxy analogues of phencyclidine, all showed strong affinity for the PCP-site on the glutamate NMDA receptor. Methoxetamine and phencyclidine and its analogues also bound appreciably to the serotonin transporter, while the PCP analogues had high affinity for sigma receptors. NMDA receptor antagonism likely explains their dissociative and psychotomimetic effects in humans; additional receptor actions may contribute to side effects.
Study at a glance
| Characteristics | In vitro pharmacological profiling Peer reviewed |
|---|---|
| Citations | 153 |
| Key finding | Novel ketamine and phencyclidine analogues are high-affinity ligands for the NMDA receptor PCP-site, which may account for their psychotomimetic effects in humans. |
Abstract
In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.