Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT₃ and 5-HT₆ Receptor Antagonist with Antipsychotic and Procognitive Properties

Abstract

In line with recent clinical trials demonstrating that ondansetron, a 5-HT 3 receptor (5-HT 3 R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT 6 receptor (5-HT 6 R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT 3 /5-HT 6 R antagonists. We identified the first-in-class compound FPPQ , which behaves as a 5-HT 3 R antagonist and a neutral antagonist 5-HT 6 R 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-HT 6 R inverse agonist SB399885 nor neutral 5-HT 6 R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT 3 R antagonism and 5-HT 6 R 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-HT 3 /5-HT 6 receptors and encourage further studies on dual-acting 5-HT 3 /5-HT 6 R antagonists for the treatment of psychiatric disorders.

Perceiving the Concealed and Unreported Pharmacophoric Features of the 5-Hydroxytryptamine Receptor Using Balanced QSAR Analysis

“…An additional advantage associated with 5-HT6 is its restricted and exclusive occurrence within the CNS, which implies that compounds acting through this receptor could have minimal peripheral side effects [2,3,6,10,12]. Even though several molecules have been identified as promising ligands with high binding affinities for 5-HT6 (see Figure 1), none of them has cleared the clinical stages or been approved as a drug [1, [7][8][9][10]12]. Therefore, there is a need to develop a novel therapeutic agent with a better ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and the retention of a high binding affinity for 5-HT6.…”

“…[ 1 , 2 , 3 , 4 ], and are facing diverse health and social challenges. Though therapeutic agents are available for the treatment of these diseases, they lack the ability to reduce the continuous loss of cognitive function, as most of them target only the acetylcholine deficit [ 2 , 3 , 5 , 6 , 7 , 8 , 9 ]. Therefore, there is a need to develop a therapeutic agent with a different mechanism of action and bio-activity profile to support the existing drug space.…”

“…Therefore, there is a need to develop a therapeutic agent with a different mechanism of action and bio-activity profile to support the existing drug space. Recently, G-protein-coupled receptors (GPCRs), viz., the serotonergic system of serotonin (5-hydroxytryptamine) receptors, have received greater attention due to their vital role in signal transduction pathways and numerous neurological functions [ 2 , 4 , 7 , 8 , 9 , 10 ]. To add further, 5-hydroxytryptamine receptors (5-HT 1–7 ) play vital roles in many cognitive dysfunctions such as memory loss, reduced learning ability, etc.…”

“…To add further, 5-hydroxytryptamine receptors (5-HT 1–7 ) play vital roles in many cognitive dysfunctions such as memory loss, reduced learning ability, etc. [ 4 , 5 , 8 , 9 ]. Among them, the 5-HT6 receptor has emerged as a promising target due to its crucial role in the onset of Alzheimer’s disease, cognitive processes, mood control, depression, and anxiety [ 4 , 5 , 8 , 9 ], to name a few.…”

“…[ 4 , 5 , 8 , 9 ]. Among them, the 5-HT6 receptor has emerged as a promising target due to its crucial role in the onset of Alzheimer’s disease, cognitive processes, mood control, depression, and anxiety [ 4 , 5 , 8 , 9 ], to name a few. It is believed that blocking the 5-HT6 receptor significantly improves learning and memory processes [ 4 , 5 , 8 , 9 ].…”