Synthesis and Structure–Activity Relationships of N-Benzyl Phenethylamines as 5-HT_2A/2C Agonists

Abstract

N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

“…Within the 2C or NBOMe drug series, para-phenyl substitutions compared with 2C-H or 25H-NBOMe, respectively, enhanced 5-HT 2 receptor binding and activation potency, which was expected based on previous studies (Blaazer et al, 2008;Eshleman et al, 2014;Hansen et al, 2014;Shulgin and Shulgin, 1991). Interestingly, 5-HT 2A receptor activation potency increased with the size of the 4-substituent (2C-D < 2C-E < 2C-P) within the 2C series (Blaazer et al, 2008;Eshleman et al, 2014), Thus, NBOMe drugs are unlike LSD, which is a potent 5-HT 1A receptor ligand and full agonist at 5-HT 1A receptors (Nichols, 2004).…”

“…Pharmacological interactions between NBOMe drugs and 5-HT 2 receptors have been well characterized for some compounds of this novel drug family (Blaazer et al, 2008;Braden et al, 2006;Ettrup et al, 2011;Ettrup et al, 2010;Hansen et al, 2014;Nichols et al, 2008). However, systematic characterizations of the effects of a larger series of NBOMe drugs at a wider range of relevant human receptors and comparisons with their 2C parent drugs are lacking.…”

Studies on the metabolism and toxicological detection of the new psychoactive designer drug 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe) in human and rat urine using GC-MS, LC-MSn, and LC-HR-MS/MS

“…They are derived from a class of the well-known potent hallucinogenic phenethylamines, the so-called 2Cs [1]. The NBOMe derivatives are very potent serotonin receptor agonists as figured out in structure-activity relationship studies [2,3]. Thus, they have a high potential for hallucinogenic effects with the risk of serotonergic toxicity.…”

PeakAL: Protons I Have Known and Loved - Fifty Shades of Grey-Market Spectra

“…This signal may result from intramolecular hydrogen bonding and proton exchange between the phenolic ortho-hydroxyl group of the NBOH moiety and the protonated amine, perhaps facilitated by the hydrogen-bond accepting solvent. However, both Heim [15] and Hansen [16,37] report a discrete and sharp phenolic peak in DMSO-d6.…”

“…[49] 1 H NMR spectra have been reported for 25B-NBOMe in DMSO-d6 [16,37] and in CDCl3 [15,50] ; for 25C-NBOMe in DMSO-d6, [37] in CDCl3, [51] and in CD3OD [16,52] ; for 25I-NBOMe in DMSO-d6, [16,37,53] in CDCl3, [15,[54][55][56] and in CD3OD [57] ; for 25I-NBOH in DMSO-d6 [15,16,37] ; for 25I-NBMD in DMSO-d6. [16,37] The 4-R family: 4-alkyl-2,5-dimethoxyphenyl pattern…”