Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT_(2A/2C) Receptor Ligands

摘要

In studies of the SAR of phenethylamine-type serotonin 5-HT_(2A) receptor agonists, substituted conformationally constrained tetrahydronaphthofurans were designed to investigate the optimal conformation of the 2-aminoethyl moiety. These compounds were tested using in vitro assays for affinity at 5-HT_(1A), 5-HT_(2A), and 5-HT_(2C) receptors. The benzofuran-containing analogues, 6a and 6b, had significantly higher affinity for the 5-HT receptors tested than did the benzodi-hydrofuran-containing compounds, 4a, 4b, 5a, and 5b. The most potent compound (8-bromo-6-methoxy-4,5-dihydro-3H-naphtho[1,8-bc]furan-5-yl)aminomethane, 6b, had K_i values for displacement of [~(125)I]-DOI from 5-HT_(2A) and 5-HT_(2C) cloned rat receptors of 2.6 and 1.1 nM, respectively. Despite their high affinity, the compounds of this naphthofuran series lacked high intrinsic activity at the 5-HT_(2A) receptor as measured using the phosphoinositide hydrolysis assay. The most potent compound in vitro, 6b, was tested in the two-lever drug discrimination assay in rats trained to discriminate LSD from saline, and failed to substitute, a result typical for compounds with low intrinsic activity. Thus, although conformational constraint has led to high-affinity 5-HT_(2A) ligands with partial agonist activity, all of the spatial and steric properties of the ligand necessary for full receptor activation have not yet been identified.