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

Anders A Jensen; John D McCorvy; Sebastian Leth Petersen; Christoffer Bundgaard; Gudrun Liebscher; Terry P Kenakin; Hans Bräuner-Osborne; Jan Kehler; Jesper L Kristensen

doi:10.1124/jpet.117.239905

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

Anders A Jensen, John D McCorvy, Sebastian Leth Petersen, Christoffer Bundgaard, Gudrun Liebscher, Terry P Kenakin, Hans Bräuner-Osborne, Jan Kehler, Jesper L Kristensen

21 Citations (Scopus)

Abstract

Therapeutic interest in augmentation of 5-hydroxytryptamine_2A (5-HT_2A) 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-HT₂receptor agonist N-2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH) and three structural analogs at recombinant 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors and investigated the pharmacokinetic properties of the compound. 25CN-NBOH displayed robust 5-HT_2A selectivity in [³H]ketanserin/[³H]mesulergine, [³H]lysergic acid diethylamide and [³H]Cimbi-36 binding assays (K_i ^2C/K_i ^2A ratio range of 52-81; K_i ^2B/K_i ^2A ratio of 37). Moreover, in inositol phosphate and intracellular Ca²⁺ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT_2A/5-HT_2C selectivities and 54-fold 5-HT_2A/5-HT_2B selectivity as measured by Δlog(R_max/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 mM) displayed a benign acute cellulartoxicological profile. 25CN-NBOH displayed high in vitro permeability (P_app = 29 × 102⁶ cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT₂A receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor.

Original language	English
Journal	Journal of Pharmacology and Experimental Therapeutics
Volume	361
Issue number	3
Pages (from-to)	441-453
ISSN	0022-3565
DOIs	https://doi.org/10.1124/jpet.117.239905
Publication status	Published - Jun 2017

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Journal Article

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Jensen, A. A., McCorvy, J. D., Petersen, S. L., Bundgaard, C., Liebscher, G., Kenakin, T. P., Bräuner-Osborne, H., Kehler, J., & Kristensen, J. L. (2017). 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. Journal of Pharmacology and Experimental Therapeutics, 361(3), 441-453. https://doi.org/10.1124/jpet.117.239905

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. / Jensen, Anders A; McCorvy, John D; Petersen, Sebastian Leth et al.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 361, No. 3, 06.2017, p. 441-453.

Research output: Contribution to journal › Journal article › Research › peer-review

Jensen, AA, McCorvy, JD, Petersen, SL, Bundgaard, C, Liebscher, G, Kenakin, TP, Bräuner-Osborne, H, Kehler, J & Kristensen, JL 2017, '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', Journal of Pharmacology and Experimental Therapeutics, vol. 361, no. 3, pp. 441-453. https://doi.org/10.1124/jpet.117.239905

Jensen AA, McCorvy JD, Petersen SL, Bundgaard C, Liebscher G, Kenakin TP et al. 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. Journal of Pharmacology and Experimental Therapeutics. 2017 Jun;361(3):441-453. doi: 10.1124/jpet.117.239905

Jensen, Anders A ; McCorvy, John D ; Petersen, Sebastian Leth et al. / 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. In: Journal of Pharmacology and Experimental Therapeutics. 2017 ; Vol. 361, No. 3. pp. 441-453.

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abstract = "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-HT2receptor agonist N-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]lysergic acid diethylamide and [3H]Cimbi-36 binding assays (Ki 2C/Ki 2A ratio range of 52-81; Ki 2B/Ki 2A ratio of 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 mM) displayed a benign acute cellulartoxicological profile. 25CN-NBOH displayed high in vitro permeability (Papp = 29 × 1026 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT2A receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor.",

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AU - Jensen, Anders A

AU - McCorvy, John D

AU - Petersen, Sebastian Leth

AU - Bundgaard, Christoffer

AU - Liebscher, Gudrun

AU - Kenakin, Terry P

AU - Bräuner-Osborne, Hans

AU - Kehler, Jan

AU - Kristensen, Jesper L

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N2 - 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-HT2receptor agonist N-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]lysergic acid diethylamide and [3H]Cimbi-36 binding assays (Ki 2C/Ki 2A ratio range of 52-81; Ki 2B/Ki 2A ratio of 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 mM) displayed a benign acute cellulartoxicological profile. 25CN-NBOH displayed high in vitro permeability (Papp = 29 × 1026 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT2A receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor.

AB - 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-HT2receptor agonist N-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]lysergic acid diethylamide and [3H]Cimbi-36 binding assays (Ki 2C/Ki 2A ratio range of 52-81; Ki 2B/Ki 2A ratio of 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 mM) displayed a benign acute cellulartoxicological profile. 25CN-NBOH displayed high in vitro permeability (Papp = 29 × 1026 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT2A receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor.

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