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Beta-oxygenated analogues of the 5-HT2A serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane.

Richard A Glennon, Mikhail L Bondarev, Nantaka Khorana, Richard Young, Jesse A May, Mark R Hellberg, Marsha A McLaughlin, Najam A Sharif

Journal of Medicinal Chemistry November 18, 2004 DOI: 10.1021/jm040082s (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Preclinical pharmacology study Peer reviewed
Population Rats (stimulus generalization test) and ocular hypertensive monkeys
Interventions 1-(4-Bromo-2 7d
Dose 300 micrograms (intraocular administration)
Measures 5-HT2A receptor binding affinity (Ki), 5-HT2-mediated calcium mobilization assay, stimulus generalization in rats, intraocular pressure
Topics Serotonin
Key points The 5-HT2A agonist 6d bound with affinity similar to R(-)DOB (Ki 0.5 vs 0.2 nM) but was over 15 times less potent in a rat test of central action; its O-methyl analog 7d was a full agonist (93% efficacy). Topical 300-microgram doses of 6d and 7d reduced intraocular pressure by 20-27% in ocular hypertensive monkeys, which the authors propose may yield minimal central effects at useful therapeutic doses.

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.

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