title: [3H]MDL 100,907: a novel selective 5-HT2A receptor ligand.
abstract: In studies using standard radioligands, unlabeled MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol) has been shown to have a high degree of selectivity for the 5-HT2A receptor. The present study was undertaken to investigate the receptor binding characteristics of [3H]MDL 100,907 in rat cortical homogenates. [3H]MDL 100,907 was found to reach equilibrium at 37 degrees C after 15 min. Saturation experiments indicated binding to a single site with a KD of 0.56 nM, Hill slope of 1.15, and a Bmax of 512 fmol/mg protein. In parallel experiments with the standard 5-HT2A receptor radioligand, [3H]ketanserin, with prazosin added to block alpha 1 receptors, a similar Hill slope and Bmax was noted but a two-fold higher KD was found. In competition binding studies using 0.5 nM [3H]MDL 100,907, some 19 standard ligands to various receptors including the 5-HT1A, D2, alpha 1, and sigma receptors resulted in estimated KI values that were consistent with [3H]MDL 100,907 selectively binding to the 5-HT2A receptor. A comparison of the KI values for 17 standard 5-HT2A receptor agonists and antagonists displacing [3H]MDL 100,907 versus [3H]ketanserin resulted in a highly significant linear correlation (R2 = 0.96, P < 0.001). Taken together these results suggest that [3H]MDL 100,907 is binding to the 5-HT2A receptor with a sub-nanomolar affinity without the use of secondary blocking agents.
authors.affiliation: Hoechst Marion Roussel, Inc., Cincinnati, OH 45215, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Johnson
authors.forename: B W
authors.initials: BW
authors.lastname: Siegel
authors.forename: A A
authors.initials: AA
authors.lastname: Carr
mesh_terms: D000818:Animals; D005464:Fluorobenzenes / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism; D007650:Ketanserin / Q000378:metabolism; D008024:Ligands; D008297:Male; D010880:Piperidines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism*
chemical_list: D005464:Fluorobenzenes; D008024:Ligands; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007650:Ketanserin; C079049:volinanserin