Novel Bivalent 5-HT2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

摘要

The 5-HT2AR plays an important role in various neuropsychiatric disorders including cocaine use disorder and schizophrenia. Homodimerization of this receptor has been suggested but tools that allow direct assessment of 5-HT2AR:5-HT2AR homodimer relevance in these disorders are necessary. We chemically modified the selective 5-HT2AR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools to probe 5-HT2AR:5-HT2AR homodimer function. We tested these molecules for 5-HT2AR antagonist activity in a cell line stably expressing the functional 5-HT2AR, and quantified a post-receptor signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK1/2), in comparison to in vivo efficacy to alter spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK1/2 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 Ki values for the binding of bivalent ligands to 5-HT2AR were only slightly lower than the values for the parent (+)-M100907 compound, but retained significant selectivity for 5-HT2AR over 5-HT2BR or 5-HT2CR binding. In addition, the 11-atom-linked bivalent 5-HT2AR antagonist (2 mg/kg, i.p.) demonstrated efficacy on par with (+)-M100907 to inhibit 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_2AR antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT_2AR structure and function.