Design, Synthesis, In Vitro, and In Silico Evaluation of a Novel Series of Serotonin 5‐HT2C Receptor (5‐HT2CR) Positive Allosteric Modulators (PAMs)

Abstract

Signal transduction and the modulation thereof characterize G protein‐coupled receptor (GPCR) function in the central nervous system (CNS) while CNS GPCRs are the therapeutic targets for most neuropsychiatric disorders. Endogenous ligands (e.g., neurotransmitters) and GPCRs are embedded into a dynamic landscape of temporally and spatially controlled signalling events that contribute to physiological brain function, and dysregulation of GPCR systems is implicated in pathophysiological states. Utilizing studies of the serotonin (5‐HT) 5‐HT2C receptor (5‐HT2CR), which has been implicated in CNS disorders such as drug use disorders and depression, we sought to discover novel modulators of 5‐HT2CR function that maintain the temporal and spatial characteristics of CNS signaling. Decreased 5‐HT2CR signaling has been implicated in dysregulated impulse control and drug‐seeking in rodent preclinical models, with selective 5‐HT2CR agonists exhibiting affinity to dampen these behavioral outcomes. The utilization of positive allosteric modulators (PAMs) is an attractive strategy to increase 5‐HT2CR functional response while limiting disruption of its dynamic signaling landscape. Our PAM discovery efforts have focused on two unique molecular scaffolds (i.e., CYD‐1‐79 and oleamide) and the derivatization of each. Synthesized, novel small molecules were screened via a cell‐based, 5‐HT‐induced, intracellular calcium (Ca2+) release assay with physiologically relevant 5‐HT2CR expression levels. Our studies have resulted in the discovery of multiple 5‐HT2CR PAMs, including CYD‐1‐79 and oleamide‐based molecular scaffolds, that increase 5‐HT2CR‐dependent function by 20% or greater. In vitro distribution, metabolism, and pharmacokinetic (DMPK) analyses and physicochemical properties indicate that our 5‐HT2CR PAMs display a range of promising lead‐ and drug‐like attributes. In silico molecular docking with the recently published 5‐HT2CR X‐ray crystal structure has identified a potential PAM binding site common to a diverse collection of small molecule 5‐HT2CR PAM derivatives. In conclusion, we have discovered and further optimized novel series of 5‐HT2CR PAMs with the potential for translation towards neurotherapeutics for drug use disorders and other CNS disorders in which 5‐HT2CR dysfunction is implicated as a mediator.Support or Funding InformationSupported by grants R01 DA038446 (JZ/KAC), K05 DA020087 (KAC), P30 DA028821 (KAC), T32 DA07287 (CTW, EAW), F31 DA038922 (CTW), F31 DA045511 (EAW)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.