β-Oxygenated Analogues of the 5-HT2A Serotonin Receptor Agonist 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane

• Published in: Journal of medicinal chemistry 2004-11, Vol.47 (24), p.6034-6041
• Main Authors: Glennon, Richard A, Bondarev, Mikhail L, Khorana, Nantaka, Young, Richard, May, Jesse A, Hellberg, Mark R, McLaughlin, Marsha A, Sharif, Najam A
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Binding, Competitive; Biological and medical sciences; Blood-Brain Barrier; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Discrimination Learning - drug effects; DOM 2,5-Dimethoxy-4-Methylamphetamine - analogs & derivatives; DOM 2,5-Dimethoxy-4-Methylamphetamine - chemical synthesis; DOM 2,5-Dimethoxy-4-Methylamphetamine - chemistry; DOM 2,5-Dimethoxy-4-Methylamphetamine - pharmacology; Eye; Intraocular Pressure - drug effects; Macaca fascicularis; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Ocular Hypertension - drug therapy; Ocular Hypertension - physiopathology; Oxygen - chemistry; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Agonists; Serotoninergic system; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040082s

Activation of 5-HT2A serotonin receptors represents a novel approach to lowering intraocular pressure. Because 5-HT2A 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-HT2A 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-HT2A 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.