2-(1-NAPHTHYLOXY)ETHYLAMINES WITH ENHANCED AFFINITY FOR HUMAN 5-HT1D-BETA (H5-HT1B) SEROTONIN RECEPTORS

Although the beta-adrenergic antagonist propranolol (1) binds at roden t 5-HT1B serotonin receptors, it displays low affinity (K-i > 10 000 n M) for its species homologue 5-HT1D beta (i.e., h5-HT1B) receptors. Th e structure of propranolol was systematically modified in an attempt t o enhance its affinity for the latter population of receptors. Removal of the alkyl hydroxyl group, shortening of the O-alkyl chain from thr ee to two methylene groups, and variation of the terminal amine substi tuent resulted in compounds, such as N-monomethyl-2-(1-naphthyloxy)eth ylamine (11; K-i = 26 nM), that display significantly higher h5-HT1B a ffinity than propranolol. Compound 11 was shown to bind equally well a t human 5-HT1D alpha (h5-HT1D) receptors (K-i = 34 nM) and was further demonstrated to possess h5-HT1B agonist character in an adenylate cyc lase assay. It would appear that such (aryloxy)alkylamines may represe nt a novel class of 5-HT1D receptor agonists.