[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.

M100907, A Selective 5-HT2A Receptor Antagonist and a Potential Antipsychotic Drug, Facilitates N-Methyl-D-Aspartate-Receptor Mediated Neurotransmission in the Rat Medial Prefrontal Cortical Neurons In Vitro

“…[R-( + )-a-(2,3-dimethoxyphenil)-1-[ 4-fluorophenylethyl)]-4-piperidinemethanol; Johnson et al 1996;Kehne et al 1996;Marek and Aghajanian 1994;Sorensen et al 1993], which is currently under phase IIB clinical studies, is an effective antipsychotic drug (APD; Dr. S. Sorensen, Hoechst Marion Roussel, personal communications). Where and how M100907 exerts its action to alleviate schizophrenic symptoms becomes a subject of fundamental importance with both theoretical and clinical relevance.…”

Molecular genetic responses to lysergic acid diethylamide include transcriptional activation of MAP kinase phosphatase‐1, C/EBP‐β and ILAD‐1, a novel gene with homology to arrestins

“…MDL100 907 (Johnson et al 1996) was obtained from Hoechst Marion Roussel (Cincinnati, OH, USA). WAY100 635 (Critchley et al 1994) RNA samples and expression testing The 1.0 mg/kg LSD time (t) ¼ 90 min and matched control RNAs were gathered in three independent experiments.…”

Synthesis, labelling and first evaluation of [18F]R91150 as a serotonin 5‐HT2A receptor antagonist for PET

“…Both MDL 100907 and altanserin bind to the 5-HT 2A receptor with high affinity. MDL 100907 exhibits a K i value of 0.2 nM 4 and a K D value of 0.56 nM (using [ 3 H]MDL 100907), 5 while altanserin has a K i of 0.13 nM 6 and a K D of 0.3 nM. 7 Binding to other 5-HT receptor subtypes is very low for MDL 100907 5 and moderate to low for altanserin.…”