The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

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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.

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Automated design of ligands to polypharmacological profiles

Jérémy Besnard, Gian Filippo Ruda, Vincent Setola … (2012)

The clinical efficacy and safety of a drug is determined by its activity profile across multiple proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to rationally design drugs a priori against profiles of multiple proteins would have immense value in drug discovery. We describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads where multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.

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Ketamine use: a review.

Celia Morgan, H. Curran (2011)

Ketamine remains an important medicine in both specialist anaesthesia and aspects of pain management. At the same time, its use as a recreational drug has spread in many parts of the world during the past few years. There are now increasing concerns about the harmful physical and psychological consequences of repeated misuse of this drug. The aim of this review was to survey and integrate the research literature on physical, psychological and social harms of both acute and chronic ketamine use. The literature on ketamine was systematically searched and findings were classified into the matrix of Nutt et al.'s (2007) rational scale for assessing the harms of psychoactive substances. A major physical harm is ketamine induced ulcerative cystitis which, although its aetiology is unclear, seems particularly associated with chronic, frequent use of the drug. Frequent, daily use is also associated with neurocognitive impairment and, most robustly, deficits in working and episodic memory. Recent studies suggest certain neurological abnormalities which may underpin these cognitive effects. Many frequent users are concerned about addiction and report trying but failing to stop using ketamine. The implications of these findings are drawn out for treatment of ketamine-induced ulcerative cystitis in which interventions from urologists and from addiction specialists should be coordinated. Neurocognitive impairment in frequent users can impact negatively upon achievement in education and at work, and also compound addiction problems. Prevention and harm minimization campaigns are needed to alert young people to these harmful and potentially chronic effects of ketamine. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

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Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.

K Baner, Paul Ernsberger, B Roth … (2002)

Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited (3)H-bremazocine binding to cloned kappa opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent kappa opioid agonist at cloned kappa opioid receptors expressed in human embryonic kidney-293 cells and at native kappa opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT(2A) serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for kappa opioid receptors, kappa opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that kappa opioid receptors play a prominent role in the modulation of human perception.

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Author and article information

Contributors

Kenji Hashimoto: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 19 March 2013

Volume: 8

Issue: 3

Electronic Location Identifier: e59334

Affiliations

[1 ]NIMH Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina, United States of America

[2 ]Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, United Kingdom

[3 ]LGC Forensics, London, United Kingdom

[4 ]Department of Pharmacology, University of Oxford, Oxford, United Kingdom

Chiba University Center for Forensic Mental Health, Japan

Author notes

* E-mail: les.iversen@ 123456pharm.ox.ac.uk

Competing Interests: One of the authors (RT) is employed by LGC Forensics though this does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. No conflict of interest arises because of his employment. All other authors deny any potential conflict of interest relating to the contents of this paper.

Conceived and designed the experiments: BLR LI. Performed the experiments: XPH VS. Analyzed the data: XPH VS. Wrote the paper: BLR SG WA XPH VS RT LI. Responsible for chemistry: WA SG RT.

Article

Publisher ID: PONE-D-12-32472

DOI: 10.1371/journal.pone.0059334

PMC ID: 3602154

PubMed ID: 23527166

SO-VID: afc9aa82-be57-4d18-8c93-df3cbda5be9d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 18 October 2012

Date accepted : 13 February 2013

Page count

Pages: 5

Funding

Supported by the NIMH Psychoactive Drug Screening Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

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Most cited references 17

Automated design of ligands to polypharmacological profiles

Ketamine use: a review.

Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.

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Cited by 34

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