Journal Article

Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues

Colestock, Tristan, Kang, Heather, Collingridge, Graham L, Halberstadt, Adam L, Brandt, Simon D, Bortolotto, Zuner A, Adejare, Adeboye, Morris, Hamilton, Wallach, Jason, Lodge, David

2016

Overview

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as 'legal highs' in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many 'legal highs', little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abuse / Acetamides - administration & dosage / Analgesics, Opioid - chemistry / Analgesics, Opioid - therapeutic use / Animals / Antagonists / Biology and Life Sciences / Brain research / Central nervous system / Channel gating / Disease control / Dopamine / Dopamine transporter / Drug abuse / Drug Overdose - genetics / Drug Overdose - pathology / Drugs / Epilepsy / Glutamate receptors / Glutamic acid receptors / Histamine / Humans / Inhibition / Isomers / Ketamine / Ketamine - administration & dosage / Ketamine - adverse effects / Legislation / Ligands / Medicine and Health Sciences / Mental depression / N-Methyl-D-aspartic acid receptors / Narcotics / Neurosciences / Norepinephrine / Opioids / Overdose / Pain / Pharmaceutical sciences / Pharmacology / Pharmacy / Phencyclidine / Phencyclidine - administration & dosage / Phencyclidine - adverse effects / Phenethylamines - administration & dosage / Physical Sciences / Physiology / Piperidines - administration & dosage / Piperidines - adverse effects / Psychotropic drugs / Psychotropic Drugs - adverse effects / Pyridines - administration & dosage / Rats / Receptors / Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors / Receptors, Serotonin - genetics / Research and Analysis Methods / Rodents / Sensorimotor gating / Serotonin / Sigma receptors / Studies / Tablets