Synthesis and pharmacological characterization of a series of geometrically constrained 5-HT(2A/2C) receptor ligands.

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Citation

Chambers JJ, Parrish JC, Jensen NH, Kurrasch-Orbaugh DM, Marona-Lewicka D, Nichols DE

Synthesis and pharmacological characterization of a series of geometrically constrained 5-HT(2A/2C) receptor ligands.

J Med Chem. 2003 Jul 31;46(16):3526-35.

PubMed ID
12877591 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Lysergic acid diethylamide5-hydroxytryptamine receptor 1AKi (nM)1.1N/AN/ADetails