Synthesis and Evaluation of Dimeric Derivatives of 5-HT_2A Receptor (5-HT_2AR) Antagonist M-100907

Abstract

It is now well accepted that at least some serotonin receptors exist in dimeric and oligmeric forms. The linking of receptor ligands has been shown to have potential in the development of selective agonists and antagonists for traditionally refractive receptors. Here we report the development of a dimeric version of the known 5-HT2AR antagonist, M-100907. Derivatives of M-100907 were synthesized to determine an appropriate site for the linker connection. Then, homodimers with polyether linkers of different lengths were functionally tested in a bioassay to determine the optimal linker length. Attachment at the catechol of M-100907 with linkers between 12 and 18 atoms in length proved to be optimal.

Peptide Inhibitors Disrupt the Serotonin 5-HT2CReceptor Interaction with Phosphatase and Tensin Homolog to Allosterically Modulate Cellular Signaling and Behavior

“…Changes in intracellular calcium ( ${\text{Ca}}_i^{2+}$) release were determined using the calcium-sensitive dye Calcium 4 (R8142; Molecular Devices) according to previously published protocols (Shashack et al, 2011; Ding et al, 2012; Seitz et al, 2012). Cells were plated in serum-replete medium at indicated densities in black-sided, clear-bottom 96-well tissue culture plates.…”

“…Addition of 5-HT [1 nM (approximate EC 50 ) for 5-HT 2C R–CHO cells or 10 nM (approximate EC 50 ) for 5-HT 2A R–CHO cells] or 20 nM WAY163909 (approximate EC 50 ) for 5-HT 2C R–CHO cells occurred at the 17 s time point, and fluorescence was recorded every 1.7 s for 90–120 s (Shashack et al, 2011; Ding et al, 2012; Seitz et al, 2012). To assess the effects of 3L4F on the concentration–response relationship for 5-HT in 5-HT 2C R–CHO cells, addition of 5-HT (10 pM to 1 μ M) occurred at the 17 s time point, and fluorescence was recorded every 1.7 s for 90–120 s (Shashack et al, 2011; Ding et al, 2012; Seitz et al, 2012). Preincubation with vehicle (HBSS), 3L4F peptide, or 3L4F peptide fragments occurred 15 min before the start of the experiment.…”

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…The enhancement observed between the 5-HT 2A R antagonist M100907 plus WAY 163909 was achieved at doses that are much lower than the doses of each ligand necessary to affect the given behavior when administered alone, suggesting that there may be combination approaches that would potentially minimize side effects of the medications. At present, there are no FDA-approved medications known to exhibit this exact pharmacological profile; however, efforts to chemically synthesize such molecules are ongoing (Booth et al, 2009;Shashack et al, 2011;Cunningham et al, 2013).…”

18F-Labeled Silicon-Based Fluoride Acceptors: Potential Opportunities for Novel Positron Emitting Radiopharmaceuticals

“…This multimeric approach is supported by the development of bivalent 5-HT ligands based on recent evidence suggesting that some 5-HT receptors exist as dimers/oligomers [67]. The tracer, [ 18 F]BMPPSiF, was obtained following the leaving group approach from the corresponding hydrosilane.…”