Chemistry and Biology of 5-HT2C Receptor Ligands for Drug Abuse

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DESCRIPTION (provided by applicant): Serotonin mediates or regulates a wide variety of behaviors including cognition, emotion, attention, and appetite among others. In addition, there is substantial data suggesting that 5-HT is involved in mediating the effects of psychomotor stimulants such as cocaine and MDMA or "ecstasy". Further, there is increasing evidence that serotonergic systems in the brain also regulate dopaminergic reward systems and other factors including the conditioning effects that environmental factors have in maintaining drug taking behavior. The 5-HT2 family of receptors represent key sites of action of serotonin in the brain, and recent evidence strongly suggests that 5-HT2 receptors are very important in controlling drug taking behavior. To date, the quest to identify pharmacotherapies for cocaine addiction has largely overlooked the prospects of medications based upon 5-HT2R pharmacology. It appears that 5-HT2 receptor functions include an excitatory role for the 5-HT2AR and an inhibitory role for the 5-HT2CR in the control of some overt stimulant- induced behaviors. Furthermore, the 5-HT2AR and 5-HT2CR may play a role in the strong conditioned associations made between cocaine and environmental stimuli ("cues"). It is also clear that drugs with high selectivity and specificity will need to be developed because interaction with several related (and unrelated) receptors can be associated with significant morbidity and mortality. For example, valvular heart disease is associated with activation of the 5-HT2B subtype and hallucinations are caused by activation of the 5-HT2AR. Based upon screening of a chemical library, we have identified tranylcypromine as a possible lead candidate in our quest to identify useful 5HT2CR ligands. After preliminary SAR work, we have identified some potent and selective 5HT2CR ligands. These preliminary efforts provide the basis of the present grant whose aim is to identify 5HT2CR ligands that can be used both as research tools and as potential therapeutics for use in treating cocaine addiction and possibly other disorders, including obesity. We will test the overarching hypothesis that compounds that act as 5-HT2CR agonists (or 5-HT2AR antagonists) will prove useful in reducing cocaine use in rat self-administration (SA) paradigms. These aims are formalized as follow: 1. Based upon the SAR now in hand, carry out additional chemistry studies with the aim of further enhancing binding affinity as well as subtype selectivity; 2. Screen new ligands for their binding affinity and if warranted, for their functional activity at the three 5HT2 receptors. 3. Those compounds with activity as 5-HT2CR agonists or 5-HT2AR antagonists will be evaluated in rats to assess behavioral activity in a series of rat experiments of increasing complexity that will determine their viability as agents useful in the reduction or prevention of cocaine abuse.