Primetime is collaborating (CRADA) with NIDDK/NIH to develop small molecule TRHR agonists that are metabolically stable and able to cross the blood-brain barrier might serve as drugs for the treatment of patients with several central nervous system disorders and obesity.
This project aims to discover small drug-like molecules that will activate (agonists) the human TRHR, a member of the 7 transmembrane-spanning receptor (7TMR) (or G protein-coupled receptor, GPCR) family of drug-accessible cell surface receptors. Many studies have linked TRH and TRHR to psychiatric disorders. For example, individuals with major depression exhibit a blunted thyrotropin (thyroid-stimulating hormone, TSH) response to TRH and absence of the nocturnal TSH surge, and decreased TRH gene expression was observed in the hypothalamus of depressed patients. TRH and TRHR in the limbic system and cortex are believed to mediate the endogenous and exogenous effects of TRH on affect, mood and arousal but it has been notoriously difficult to assign specific functions and behaviors to extrahypothalamic TRH. TRH has also been shown to be anorexigenic in rodents. Small molecule TRHR agonists that are metabolically stable and able to cross the blood-brain barrier might serve as probes to elucidate the roles of TRH receptors in the brains in animal models and might be valuable as lead compounds for the development of drugs to treat patients with several central nervous system (CNS) disorders and obesity. It is important to note that there are no known nonpeptidic agonists of TRHR.