title: Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.
abstract: 3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT2receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT2a,b,cand NEα2receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT2a,b,creceptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT2creceptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC50determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT2a,creceptors as compared to MDMA.
authors.affiliation: Department of Toxicology, Kimron Veterinary Institute, Bet Dagan, Israel. jakobs@moag.gov.il.
authors.forename: Jakob A
authors.initials: JA
authors.lastname: Shimshoni
authors.affiliation: Pharmaseed Ltd, Ness Ziona, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Winkler
authors.affiliation: BSC BV Company, Veemarkt 61, Amsterdam, Netherlands.
authors.forename: Ezekiel
authors.initials: E
authors.lastname: Golan
authors.affiliation: Neuropsychopharmacology Unit, Imperial College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Nutt
mesh_terms: D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002394:Catechol O-Methyltransferase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011869:Radioligand Assay; D044348:Receptors, Serotonin, 5-HT2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001572:Benzofurans; D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D044348:Receptors, Serotonin, 5-HT2; D058826:Serotonin 5-HT2 Receptor Agonists; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: 3,4-Methylenedioxy-N-methylamphetamine (MDMA); MDMA analogues; Monoamine receptors; Monoamine transporters; Neurochemical profile