title: Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs).
abstract: BACKGROUND
  N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used psychoactive substances with poorly defined pharmacological properties. The aim of the present study was to characterize the receptor binding profiles of a series of NBOMe drugs compared with their 2,5-dimethoxy-phenethylamine analogs (2C drugs) and lysergic acid diethylamide (LSD) in vitro.
  
  
  METHODS
  We investigated the binding affinities of 2C drugs (2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, and mescaline), their NBOMe analogs, and LSD at monoamine receptors and determined functional 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2B receptor activation. Binding at and the inhibition of monoamine uptake transporters were also determined. Human cells that were transfected with the respective human receptors or transporters were used (with the exception of trace amine-associated receptor-1 [TAAR1], in which rat/mouse receptors were used).
  
  
  RESULTS
  All of the compounds potently interacted with serotonergic 5-HT2A, 5-HT2B, 5-HT2C receptors and rat TAAR1 (most Ki and EC50: <1 μM). The N-2-methoxybenzyl substitution of 2C drugs increased the binding affinity at serotonergic 5-HT2A, 5-HT2C, adrenergic α1, dopaminergic D1-3, and histaminergic H1 receptors and monoamine transporters but reduced binding to 5-HT1A receptors and TAAR1. As a result, NBOMe drugs were very potent 5-HT2A receptor agonists (EC50: 0.04-0.5 μM) with high 5-HT2A/5-HT1A selectivity and affinity for adrenergic α1 receptors (Ki: 0.3-0.9 μM) and TAAR1 (Ki: 0.06-2.2 μM), similar to LSD, but not dopaminergic D1-3 receptors (most Ki:>1 μM), unlike LSD.
  
  
  CONCLUSIONS
  The binding profile of NBOMe drugs predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties because of α1 receptor interactions.
authors: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors: Anna
authors: A
authors: Rickli
authors: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors: Dino
authors: D
authors: Luethi
authors: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors: Julian
authors: J
authors: Reinisch
authors: Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors: Danièle
authors: D
authors: Buchy
authors: Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors: Marius C
authors: MC
authors: Hoener
authors: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address: matthias.liechti@usb.ch.
authors: Matthias E
authors: ME
authors: Liechti
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism
chemical_list: D014179:Neurotransmitter Uptake Inhibitors; D010627:Phenethylamines; D011619:Psychotropic Drugs; D044348:Receptors, Serotonin, 5-HT2; D044282:Receptor, Serotonin, 5-HT1A
keywords: Affinity; Hallucinogens; Novel psychoactive substances; Phenethylamines; Receptor