Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues.
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.
Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia Pennsylvania, United States of America.
Jason
http://orcid.org/0000-0002-2467-5761
J
Wallach
Centre for Synaptic Plasticity, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
Heather
H
Kang
Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia Pennsylvania, United States of America.
Tristan
T
Colestock
Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia Pennsylvania, United States of America.
Hamilton
H
Morris
Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
Zuner A
ZA
Bortolotto
Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.|Department of Physiology, Faculty of Medicine, Toronto, Ontario, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Graham L
http://orcid.org/0000-0002-9572-5359
GL
Collingridge
Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
David
D
Lodge
Department of Psychiatry, University of California San Diego, La Jolla, California, United States Of America.
Adam L
AL
Halberstadt
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, United Kingdom.
Simon D
SD
Brandt
Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia Pennsylvania, United States of America.
Adeboye
http://orcid.org/0000-0002-7732-8974
A
Adejare
D000081:Acetamides / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D062787:Drug Overdose / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects; D010622:Phencyclidine / Q000008:administration & dosage / Q000009:adverse effects; D010627:Phenethylamines / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011619:Psychotropic Drugs / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011985:Receptors, Serotonin / Q000235:genetics
C585977:AZD6765; D000081:Acetamides; D000701:Analgesics, Opioid; D010627:Phenethylamines; D010880:Piperidines; D011619:Psychotropic Drugs; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; C011896:lephetamine; D007649:Ketamine; C067553:remacemide; C000595747:1-(1-(2-methoxyphenyl)-2-phenylethyl)piperidine; C000599677:diphenidine; D010622:Phencyclidine