Work

Dually Acting Ligands Targeting Serotonin Receptors: Implications in CNS Disorders

Year: 2026

Type: article

Abstract: The serotonergic system remains a critical focus of neuropsychopharmacology due to its widespread influence on mood, cognition, and behavior. Despite the clinical success of selective serotonin reuptake inhibitors (SSRIs), their long-term efficacy is limited by receptor heterogeneity, desensitization, and compensatory adaptations. Recent advances suggest that ligands simultaneously modulating two serotonin (5-HT) receptor subtypes may offer superior therapeutic outcomes. This perspective summarizes progress in developing such dually acting compounds for CNS disorders, including Alzheimer’s and Parkinson’s disease, schizophrenia, and mood disorders. Clinically relevant examples include flibanserin (5-HT 1A receptor agonist/5-HT 2A receptor antagonist), pimavanserin (5-HT 2A /5-HT 2C receptors inverse agonist), and eltoprazine (5-HT 1A /5-HT 1B receptors partial agonist), alongside experimental 5-HT 2A /5-HT 6, 5-HT 3 /5-HT 6 or TAAR1/5-HT 2C receptors ligands. Integrating structure–activity insights and clinical findings, we discuss challenges of rational dual modulation. Advances in biased signaling, targeting distinctive conformational states, and optopharmacology utilizing photochromic ligands may further enable the design of innovative dually acting agents with improved efficacy and safety profiles.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c03094

Authors: Wojciech Trybała, Katarzyna Grychowska, Natalia Malikowska-Racia, Agnieszka Nikiforuk, Piotr Popik, Paweł Zajdel

Institutions: Jagiellonian University, Maj Institute of Pharmacology, Polish Academy of Sciences

Language: English

Topic: Neurotransmitter Receptor Influence on Behavior

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500