Novel Bivalent 5-HT 2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

Claudia A. Soto, Matthew J. Shashack, Robert G. Fox, Marcy J. Bubar, Kenner C. Rice, Cheryl S. Watson, Kathryn A. Cunningham, Scott R. Gilbertson, Noelle C. Anastasio

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


The 5-HT 2A receptor (5-HT 2A R) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HT 2A R:5-HT 2A R homodimer in these disorders are necessary. We chemically modified the selective 5-HT 2A R antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HT 2A R:5-HT 2A R homodimer function. We tested these molecules for 5-HT 2A R antagonist activity in a cell line stably expressing the functional 5-HT 2A R and quantified a downstream signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK 1/2 ), in comparison to in vivo efficacy of altering spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK 1/2 in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length, with the intermediate linker lengths being the most potent. The K i values for the binding of bivalent ligands to 5-HT 2A R were only slightly lower than the values for the parent (+)-M100907 compound, but significant selectivity for 5-HT 2A R over 5-HT 2B R or 5-HT 2C R binding was retained. In addition, the 11-atom-linked bivalent 5-HT 2A R antagonist (2 mg/kg, intraperitoneally) demonstrated efficacy on par with that of (+)-M100907 in inhibiting cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HT 2A R antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT 2A R structure and function.

Original languageEnglish (US)
Pages (from-to)514-521
Number of pages8
JournalACS chemical neuroscience
Issue number3
StatePublished - Mar 21 2018

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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