Abstract
In line with recent clinical trials demonstrating that ondansetron, a 5-HT3 receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.
Highlights
Schizophrenia is a debilitating mental disorder characterized by the presence of positive and negative symptoms that are usually accompanied by cognitive impairment
A detailed analysis of the receptor profile of clozapine, the only antipsychotic used in treatment-resistant schizophrenia,[2,3] in addition to well-known blockade of serotonin type 2A (5HT2A) receptor, revealed the antagonistic properties at the serotonin type 3 receptor (5-HT3R)[4] and serotonin type 6 receptor (5-HT6R).[5]
As the a priori hypothesis was that the combined treatment with 5-HT6 receptor (5-HT6R) and 5-HT3 receptor (5-HT3R) antagonists would produce different effects than their individual actions and/or vehicle, we analyzed the SB399885-induced potentiation of PCP hyperactivity and its inhibition by ondansetron addition, using analyses of contrast coefficients[51] on time-collapsed Area Under Curve (AUC) data
Summary
Schizophrenia is a debilitating mental disorder characterized by the presence of positive (hallucinations, delusions) and negative (social withdrawal, flat affect, low motivation) symptoms that are usually accompanied by cognitive impairment (e.g., learning and attention deficits). As the a priori hypothesis was that the combined treatment with 5-HT6R and 5-HT3R antagonists would produce different effects than their individual actions and/or vehicle, we analyzed the SB399885-induced potentiation of PCP hyperactivity and its inhibition by ondansetron addition, using analyses of contrast coefficients[51] on time-collapsed AUC data. As the a priori hypothesis was that the combined treatment with 5-HT6R and 5-HT3R antagonists would produce different effects than their individual actions and/or vehicle, we analyzed 0−120 min AUC activity data with contrast coefficients These planned comparisons revealed that combined treatment with CPPQ (0.3 mg/kg) and ondansetron (0.5 mg/kg) inhibited PCP-induced hyperactivity compared with vehicle (Figure 11C). The procognitive effect of the antidepressant drug vortioxetine results from its antagonistic properties at 5-HT3R in the GABAergic interneurons of the mPFC.[55,56] blockade of both 5-HT3R and 5HT6R may contribute to the procognitive effect of FPPQ
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call