Insights into the structure and function of 5-HT₂ familyserotonin receptors reveal novel strategies for therapeutic target development

Abstract

5-HT₂ family serotonin receptors, principal sites of action of serotonin in the brain, represent major molecular targets for drugs used in treating a variety of diseases including schizophrenia, depression, anxiety, eating disorders, obsessive-compulsive disorder, chronic pain conditions and obesity. The 5-HT₂ family of receptors has three members: 5-HT_2A, 5-HT_2B and 5-HT_2C. Therefore, it is likely that subtype-selective compounds will be needed to avoid serious side effects and to enhance therapeutic indices. Unfortunately, recent insights into the structure and function of 5-HT_2A receptors have revealed that structurally-diverse agonists and antagonists have distinct modes of interacting with 5-HT_2A receptors, complicating efforts at structure-based drug-design. These distinct binding modes would not have been predicted based on conventional structure-activity relationships or static docking models. Fortunately, these complicated binding modes can be predicted and simulated using molecular dynamics, allowing for the possibility of structure-based drug design. Thus, provided appropriately sophisticated drug design strategies are employed, it is likely that uniquely valuable medications will result which could have great potential for treating a variety of mental and physical illnesses.

• antipsychotic agents
• anxiolytics
• obsessive-compulsive disorder
• serotonin
• structure