title: Synthesis and pharmacological characterization of a series of geometrically constrained 5-HT(2A/2C) receptor ligands.
abstract: 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 benzodihydrofuran-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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-1333, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Chambers
authors.forename: Jason C
authors.initials: JC
authors.lastname: Parrish
authors.forename: Niels H
authors.initials: NH
authors.lastname: Jensen
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Kurrasch-Orbaugh
authors.forename: Danuta
authors.initials: D
authors.lastname: Marona-Lewicka
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D004193:Discrimination Learning / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D008024:Ligands; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C476601:(8-bromo-6-methoxy-4,5-dihydro-3H-naphthol(1,8-bc)furan-5-yl)aminomethane; D005663:Furans; D006575:Heterocyclic Compounds, 3-Ring; D007295:Inositol Phosphates; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D008238:Lysergic Acid Diethylamide