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PAP-1 is a small molecule Kv1.3 blocker that was developed through classical medicinal chemistry from the medicinal plant Ruta graveolens (= the common rue or the herb of grace). Instigated by anecdotal reports from Chile and Austria in 1987 that tea prepared from Ruta graveolens supposedly have beneficial effects in patients with multiple sclerosis, a group of scientists at the University of Kiel in Germany started extracting Ruta and screening the extracts for potassium channel blockers. The investigators identified 5-methoxypsoralen (5-MOP) as the active principle of the plant and demonstrated in off-label single-case studies that 5-MOP improves visual field defects in multiple sclerosis patients. However, since 5-MOP was not suitable for the long-term treatment of MS because of its phototoxicity (= interaction with DNA under UVA irradiation), we designed derivatives of 5-MOP that are not phototoxic and considerably more potent and selective.
The most potent and drug-like of these novel derivatives is PAP-1, which inhibits Kv1.3 with an EC50 of 2 nM and displays an excellent selectivity over other potassium channels. |
