Chiral aryloxyalkylamines: Selective 5-HT(1B/1D) activation and analgesic activity

A series of chiral 2,3-dichlorophenoxy and 1-naphthyloxy alkylamines were synthesized, and their binding affinities towards 5-HT(1D) and h5-HT(1B) receptors were evaluated. In the naphthyloxy series, the (R)-prolinol derivative was the most selective 5-HT(1D) ligand, while (S)-N-methyl-2-(1-naphthyloxy)propan-1-amine showed the highest selectivity for h5-HT(1B). Both compounds performed as 5-HT(1D) agonists in the isolated guinea pig assay and showed higher analgesic activity than both sumatriptan and the achiral analogue 20 b in the mouse hot-plate test. Neither ligand displayed any affinity for nicotinic ACh receptors present in mouse brain membranes, thus indicating that their analgesic activity does not arise through interaction with these receptors.