β-Oxygenated Analogues of the 5-HT_2A Serotonin Receptor Agonist 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane

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-HT₂ 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-HT₂ 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-HT₂-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 μg 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.