5-HT2 Receptor Allosterism in Cocaine Use Disorder

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Cocaine use disorder (CUD) is diagnosed by clinical indicators (e.g., risky drug use, social/interpersonal difficulties linked to use, withdrawal/tolerance, failed efforts to control use, etc.), while craving (a strong desire or urge to take a drug) and relapse which can be linked to elevated stress and negative affect and compounded by exposure to cocaine and cocaine-associated environmental cues. Our team and others established that dampened signaling through the serotonin (5-HT) 5-HT2C receptor (5-HT2CR), a member of the 5-HT2R family, is a key element of the mechanisms of action underlying cognitive and behavioral vulnerability to CUD and relapse. We pioneered the development of positive allosteric modulators (PAMs) for the 5-HT2CR and discovered our first generation of 5-HT2CR PAMs to bind to an identified, spatially distinct allosteric site to selectively potentiate 5-HT2CR, but not 5-HT2AR or 5-HT2BR, signaling in vitro without intrinsic activity at the three these receptors. As a proof-of-concept, two of our 5-HT2CR PAMs (CYD-1-79, CTW0415) potentiated in vivo effects of a full 5-HT2CR agonist in male rats, an effect which was blocked by a selective 5-HT2CR antagonist, verifying reliance on 5-HT2CR function. CYD-1-79 also suppressed cocaine-seeking in a relapse-like behavioral model in male rats. Our objectives are to optimize 5-HT2CR PAMs with favorable drug-like properties and analyze select molecules in proof-of-concept in vivo assays and models of CUD. To accomplish our goals, we will pursue three aims to discover next generation 5-HT2CR PAMs for illumination of 5-HT2CR allosterism, optimize 5-HT2CR PAMs with favorable drug metabolism and pharmacokinetics profiles which will be assessed for efficacy in rodent preclinical models of CUD. There is a gap in our ability to maximize therapeutic strategies to reduce the psychological and medical impact of CUD in patients. We address this gap in treatment efficacy by presenting the novel concept that 5-HT2CR may prove useful in treating CUD. Importantly, the advances in novel molecule discovery and expansion of knowledge of allosteric modulation of the 5-HT2CR systems could have a profound impact in improving the course and treatment of an even broader category of neuropsychiatric disorders.