ARYLOXYETHYLAMINES AS H5-HT1D SEROTONIN RECEPTOR LIGANDS

We have previously demonstrated that naphthyloxyethylamines, such as N -methyl-2-(1-naphthyloxy)ethylamine (2; Ri = 31 nM), represent a new c lass of h5-HT1D agonists. In the present study we show that the naphth yl ring is not a requirement for binding and that it can be replaced b y a 2,3-dichlorophenyl group without untoward effect on affinity. As w ith the naphthyloxyethylamines, none of the dichlorophenyl derivatives displayed > 10-fold selectivity for h5-HT1D (i.e., 5-HT1D alpha) rece ptors versus h5-HT1B (i.e., 5-HT1D beta) receptors. We also examined s everal conformationally-constrained analogs of 2 and show that one of these, thylaminomethyl-3,4-dihydro-2H-naphtho[1,2-b]pyran (7; Ki = 10 nM) binds at h5-HT1D receptors with several fold higher affinity than the parent compound. Compound 8 (Ki = 4 nM), the 7,8,9,10-tetrahydro d erivative of 7, was serendipitously found to bind with even higher aff inity.