Search

Pharmacophore models for 5-HT 2A receptor antagonists consist of two aromatic/hydrophobic regions at a given distance from a basic amine. We have previously shown that both aromatic/hydrophobic moieties are unnecessary for binding or antagonist action. Here, we deconstructed the 5-HT 2A receptor antagonist/serotonin-dopamine antipsychotic agent risperidone into smaller structural segments that were tested for 5-HT 2A receptor affinity and function. We show, again, that the entire risperidone structure is unnecessary for retention of affinity or antagonist action. Replacement of the 6-fluoro-3-(4-piperidinyl)-1,2-benz[ d]isoxazole moiety by isosteric tryptamines resulted in retention of affinity and antagonist action. Additionally, 3-(4-piperidinyl)-1,2-benz[ d]isoxazole (10), which represents less than half the structural features of risperidone, retains both affinity and antagonist actions. 5-HT 2A receptor homology modeling/docking studies suggest that 10 binds in a manner similar to risperidone and that there is a large cavity to accept various N 4 -substituted analogues of 10 such as risperidone and related agents. Alterations of this "extended" moiety improve receptor binding and functional potency. We propose a new risperidone-based pharmacophore for 5-HT 2A receptor antagonist action.

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.

Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression.