Design, Synthesis, and Pharmacological Characterization of Serotonin (5-HT) 5-HT2C Receptor (5-HT2CR) Positive Allosteric Modulators
A decreased signaling capacity at the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) regulates neurobehavioral processes that may underlie chronic health issues such as impulsivity disorders, drug addiction, depression, schizophrenia, and obesity. Therefore, restoration of the diminished signaling capacity through 5-HT2CR activation has therapeutic potential. A series of new molecules based on the 4-alkylpiperidine-2- carboxamide scaffold and oleamide were designed, synthesized, and pharmacologically evaluated as 5-HT2CR positive allosteric modulators (PAMs). Several analogues potentiated intracellular calcium release by 5-HT in h5-HT2CR-CHO cells. Several compounds exhibited a favorable overall pharmacokinetic profile and modulated 5-HT2CRassociated behaviors (e.g., spontaneous motor activity and drug discrimination) in rats. Two predicted allosteric sites were identified by molecular docking to a 5-HT2CR homology model. Taken together, these data represent the only combination of in vitro and in vivo evidence of a synthetic small molecule acting as a 5-HT2CR PAM providing a proof of concept that allosteric modulation of 5-HT2CR is a viable strategy toward the discovery of novel neurotherapeutics.