Synthesis and activity of functionalizable derivatives of the serotonin (5-HT) 5-HT 2A receptor (5-HT 2A R) antagonist M100907

Abstract

The approach of tethering together two known receptor ligands, to be used as molecular probes for the study of G protein-coupled receptor (GPCR) systems, has proven to be a valuable approach. Selective ligands that possess functionality that can be used to link to other ligands, are useful in the development of novel antagonists and agonists. Such molecules can also be attached to reporter molecules, such as fluorophores, for the study of GPCR dimerization and its role in signaling. The highly selective serotonin (5-HT) 5-HT receptor (5-HTR) antagonist M100907 (volinanserin) is of clinical interest in the treatment of neurological and mental health disorders. Here, we synthesized the most active (+)-M100907 enantiomer as well as a series of derivatives that possessed either an alkyne or an azide. The triazole resulting from the dipolar cycloaddition of these groups did not interfere with the ability of the bivalent ligand to act as an antagonist. Thus, we have synthesized a number of compounds which will prove useful in elucidating the role of the 5-HTR in the central nervous system.

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

“…Volinanserin (also known as M100907) is a strong 5-HT2AR receptor antagonist for the treatment of diseases such as sleep disorders and schizophrenia. Gilbertson et al 140 synthesised active, selective (+)-volinanserin enantiomer along with a series of derivatives containing a 1,2,3-triazole ring, which were evaluated to elucidate and develop their activity on 5-HT2AR in the CNS. However, in this investigation, the prepared samples did not exert the antagonistic ability of the bivalent ligand.…”

Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT2A/mGlu2 Receptor Complex

“…The heterobivalent ligands were designed to comprise the potent 5-HT 2A -selective antagonist MDL-100,907 (volinanserin) as the 5-HT 2A head group (Figure A). This compound is attractive for this purpose, as it has previously been incorporated successfully into homobivalent 5-HT 2A ligands, using the meta -methoxy position as the anchor point for the spacer. − Furthermore, it has been reported that the secondary chiral alcohol in MDL-100,907 can successfully be substituted for a carbonyl group …”

A novel electrochemical sensor based on metal nanoparticles and molecularly imprinted polymer nanocomposite with biological applications

“…An anodic peak was observed at -0.5 V due to the OH groups of PATP which reacted electrochemically on the surface electrode. Another anodic peak was observed at 0.4 V, which should be related to the redox reaction of the catechol group on the 5-HT molecule (Gilbertson et al, 2018).…”