TARGETING DOPAMINE D2 RECEPTOR IN SCHIZOPHRENIA: A THERAPEUTIC EVALUATION OF TERFENADINE

Abstract

Schizophrenia is a chronic and debilitating psychiatric disorder that affects millions worldwide. Characterized by a spectrum of symptoms—positive (hallucinations, delusions), negative (emotional flatness, social withdrawal), and cognitive (attention and memory deficits)—its pathophysiology is strongly linked to dopaminergic dysfunction, particularly the hyperactivity of dopamine D2 receptors (D2R) in the mesolimbic pathway. Current antipsychotic treatments predominantly target D2R to alleviate positive symptoms, yet many are associated with severe side effects such as extrapyramidal symptoms, metabolic syndromes, and poor compliance, necessitating the search for safer and more effective therapeutic alternatives. This study explores the potential of terfenadine, a second-generation antihistamine, as a repurposed therapeutic agent targeting D2R in the treatment of schizophrenia. Although terfenadine was originally used for allergic conditions, its structural and pharmacological properties suggest possible interaction with CNS receptors, including dopaminergic sites. The evaluation involved a comprehensive in silico approach using BIOVIA Discovery Studio, 2 focusing on molecular docking to assess binding affinity and interaction specificity of terfenadine with the D2R protein. The interaction profile was compared with established antipsychotics such as haloperidol, bromoperidol, and moperone to validate its therapeutic relevance. Docking simulations revealed that terfenadine interacts with key amino acid residues in the D2R binding pocket—particularly Asp114, Phe389, and Ser193—through hydrogen bonding and hydrophobic interactions, with a binding energy profile comparable to typical antipsychotics. The spatial orientation and conformational fit of terfenadine within the active site indicate potential antagonistic behavior, which could help reduce dopaminergic overactivity associated with the positive symptoms of schizophrenia. The findings support the hypothesis that terfenadine may serve as a viable candidate for drug repurposing in antipsychotic therapy. Its established pharmacokinetics and historical clinical use could accelerate its repositioning pathway, provided further in vitro and in vivo validation confirms efficacy and safety in psychiatric applications. Moreover, this study demonstrates the utility of molecular docking and visualization tools as cost-effective and efficient strategies in early-stage drug discovery and repositioning for neuropsychiatric disorders. In conclusion, targeting D2R remains a key strategy in the management of schizophrenia. The favorable interaction of terfenadine with D2R provides promising evidence for its potential as a novel therapeutic agent, offering a foundation for future research and development aimed at improving outcomes for individuals affected by schizophrenia.