β-Oxygenated Analogues of the 5-HT_2ASerotonin Receptor Agonist 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane

Abstract

Activation of 5-HT(2A) serotonin receptors represents a novel approach to lowering intraocular pressure. Because 5-HT(2A) serotonin receptor agonists might also produce undesirable central effects should sufficient quantities enter the brain, attempts were made to identify 5-HT(2) serotonin receptor agonists with reduced propensity to penetrate the blood-brain barrier. 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropan-1-ol (6), an analogue of the 5-HT(2) serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a) bearing a benzylic hydroxyl group, was identified as a candidate structure. Of the four optical isomers of 6, the 1R,2R-isomer (6d; K(i) = 0.5 nM) was found to bind at 5-HT(2A) receptors with an affinity similar to that of R(-)DOB (K(i) = 0.2 nM). Like R(-)DOB, 6d behaved as a partial agonist (efficacy ca. 50%) in a 5-HT(2)-mediated calcium mobilization assay. However, in an in vivo test of central action (i.e., stimulus generalization with rats as subjects), 6d was >15 times less potent than R(-)DOB. O-Methylation of 6d (i.e., 7d; 5-HT(2A) K(i) = 0.3 nM) resulted in an agent that behaved as a full (93% efficacy) agonist. Intraocular administration of 300 microg of 6d and 7d to ocular hypertensive monkeys was shown to reduce intraocular pressure by 20-27%. Given the route of administration (i.e., topical), and concentrations necessary to reduce intraocular pressure, compounds such as 6d should demonstrate minimal central effects at potentially useful therapeutic doses and offer useful leads for further development.

Structure–activity relationships of serotonin 5‐HT2A agonists

“…Glennon et al 52 have studied the effect of β-oxygenation on the 5-HT 2A agonist properties of 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB) (Figure 16). The four stereoisomers of the β-oxygenated compounds were studied, either with a β-OH or a β-OCH 3 .…”

Identification of pyrolysis products of the new psychoactive substance 2‐amino‐1‐(4‐bromo‐2,5‐dimethoxyphenyl)ethanone hydrochloride (bk‐2C‐B) and its iodo analogue bk‐2C‐I

“…[9] The synthesis of bk-2C-B was first published in 2004 where it served as an intermediate for the preparation of 2-(4-bromo-2,5-dimethoxyphenyl)morpholine. [10] The synthesis and extensive analytical characterization of bk-2C-B, verifying the identification of this substance obtained from a test purchase from an Internet vendor, was reported more recently. Furthermore, it was reported that bk-2C-B was prone degradation when analyzed by GC-MS without derivatization.…”

“…The retention times increased as a reflection of increased mass of the iodine substituent. Products analogous to bk-2C-B (1-4), (6)(7)(8) and (10) were also formed during the pyrolysis of bk-2C-I. Two additional pyrolysis products were detected and tentatively identified through interpretation of their EI mass spectra.…”

“…A sample of bk-2C-I was donated by an Internet retailer in 2015. (9) This was prepared via the sulfuryl chloride method previously reported for 2-chloro-1-(4-methylphenyl)propanone [16] 5-(4-Bromo-2,5-dimethoxyphenyl)oxazole (10) A mixture of 2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrobromide (177 mg, 0.5 mmol), p-toluenesulfonic acid (5 mg) and triethyl orthoformate (2 mL) was heated at 140°C for 3 h. The volatiles were removed under vacuum and the residue was purified by preparative TLC (silica gel; cyclohexane/EtOAc, 1/1) to afford a light-brown solid ( A mixture of 2-(4-bromo-2,5-dimethoxyphenyl)ethanol (130 mg, 0.5 mmol, prepared by the reduction of 2-(4-bromo-2,5-dimethoxyphenyl)acetic acid with borane-THF) and thionyl chloride (2 mL) was refluxed for 2 h. (Ar-CH), 110.26 (Ar-C), 57.01 (OMe), 56.04 (OMe), 43.46 (CH 2 ), 30.33 (CH 2 ). For this compound, sufficient ionization under the employed HR-ESI-MS conditions was not observed for high accuracy mass analysis.…”

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

“…[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…”