Dually Acting Ligands Targeting Serotonin Receptors: Implications in CNS Disorders.
Perspective summarizing development and design strategies for ligands that simultaneously target two serotonin receptor subtypes, citing clinical examples (flibanserin, pimavanserin, eltoprazine) and emerging approaches like biased signaling and optopharmacology with relevance to CNS disorders…
What the AI sees
Perspective summarizing development and design strategies for ligands that simultaneously target two serotonin receptor subtypes, citing clinical examples (flibanserin, pimavanserin, eltoprazine) and emerging approaches like biased signaling and optopharmacology with relevance to CNS disorders…
Research significance
Useful for Parkinson's therapeutic discovery because it highlights clinically relevant serotonergic agents (notably pimavanserin) and rational multi-target design/repurposing opportunities for symptomatic management, though it lacks new preclinical or disease‑modifying mechanisms (e.g.,…
Source 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-HT1A receptor agonist/5-HT2A receptor antagonist), pimavanserin (5-HT2A/5-HT2C receptors inverse agonist), and eltoprazine (5-HT1A/5-HT1B receptors partial agonist), alongside experimental 5-HT2A/5-HT6, 5-HT3/5-HT6 or TAAR1/5-HT2C 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.