Detailed characterization of the in vitro pharmacological and pharmacokinetic properties of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH), a highly selective and brain-penetrant 5-HT2A receptor agonist

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Therapeutic interest in augmentation of 5-hydroxytryptamine2A (5-HT2A) receptor signaling has been renewed by the effectiveness of psychedelic drugs in the treatment of various psychiatric conditions. In this study, we have further characterized the pharmacological properties of the recently developed 5-HT2 receptor agonist 2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH) and three structural analogs at recombinant 5-HT2A, 5- HT2B and 5-HT2C receptors and investigated the pharmacokinetic properties of the compound. 25CN-NBOH displayed robust 5-HT2A selectivity in [3H]ketanserin/[3H]mesulergine, [3H]LSD and [3H]Cimbi-36 binding assays (Ki 2C/Ki 2A ratio range 52-81, Ki 2B/Ki 2A ratio 37). Moreover, in inositol phosphate and intracellular Ca2+ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT2A/5-HT2C selectivities and 54-fold 5-HT2A/5-HT2B selectivity as measured by Δlog(Rmax/EC50) values. In an off-target screening 25CN-NBOH (10 μM) displayed either substantially weaker activity or inactivity at a plethora of other receptors, transporters and kinases. In a toxicological screening, 25CN-NBOH (100 μM) displayed a benign acute cellular toxicological profile. 25CNNBOH displayed high in vitro permeability (Papp = 29 x 10-6 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barrier. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57 mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 min, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CNNBOH appears to be a superior selective and brain-penetrant 5-HT2A receptor agonist compared to DOI, and thus we propose that the compound could be a valuable tool for future investigations of physiological functions mediated by this receptor.

Original languageEnglish
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Pages (from-to)441-453
Publication statusPublished - 2017

    Research areas

  • Journal Article

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