Emerging knowledge of the contribution of the serotonergic neurobiology of addiction can be utilized todesign new pharmacotherapies based upon serotonergic mechanisms. Preclinical findings strongly suggestthat a 5-HT2AR antagonist, a 5-HT2cR agonist or ligands with a combination of these actions might be auseful approach to reduce craving and enhance abstinence in addiction. The goal of Project 3 of theTranslational Center for Serotonin and Stimulant Addiction (TCSSA) is to utilize medicinal chemistrymethodology to create a series of bivalent homodimers of two 5-HT2AR antagonist molecules or two 5-HT2cRagonist molecules with the promise of increased selectivity for these receptors, as well as a series of bivalentheterodimers containing a selective 5-HTaAR antagonist molecule and a 5-HT2CR agonist molecule. Thedimers will be based on the highly selective 5-HT^R antagonist M100907 and 5-HT2CR agonist WAY 470.Given the limited knowledge of how 5-HT ligands interact with their respective receptors, two derivatives ofeach molecule will be examined. These analogs will differ based upon the point of connection of the tether tothe molecule. Prior to synthesizing dimers linked at these locations, the corresponding monomer controlspossessing a model for the tether will be synthesized and evaluated to determine which locations ofattachment are benign. Project 3 will work closely with Core B to screen these new molecules for functionalactivity at wild-type 5-HT^R and 5-HT2CR, as well as at 5-HT^R and 5-HT2CR with genetic polymorphismsthat characterize the cocaine-dependent population (Project 1). This discovery research will create importantmechanistic understanding of the serotonergic system and its role in addiction biology (with Core B, Project2) and bring these together with clinical insights and facilitate 'proof-of-concept' in humans (Project 1).Project 3 represents a high risk/exploratory project and a translational bridge between human and animalpsychopharmacology, medicinal chemistry, molecular biology and pharmacology which allows the rationaldesign of new molecules and drives innovation at the interfaces of biology and chemistry as well asbiomedical and clinical research. With the knowledge gained during this developmental period, we will buildupon our new understanding of the molecular, cellular and structural biology of the 5-HT2AR and 5-HT2CRand the emerging biology of dimerization in living systems to propose additional strategies for discovery.Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currentlyavailable. We will design and create new drugs with the promise to enhance abstinence and reduce relapsein cocaine dependence.
Showing the most recent 10 out of 28 publications
