Year: 2017
Type: dissertation
Abstract: TAAR1 is a G-protein coupled receptor expressed in monoaminergic regions in the brain and represents a potential novel therapeutic target for the treatment of neurological disorders. While success has been made with discovering novel selective agonists for TAAR1, only one TAAR1 antagonist has been described thus far. We used an in silico screen on a TAAR1 homology model and identified several novel agonists and potential antagonists for TAAR1. One of the identified antagonists (compound 22) was predicted to have favourable physicochemical properties that should allow it to cross the blood brain barrier. In vivo studies were therefore carried out and showed that compound 22 potentiates amphetamine- and cocaine-mediated locomotor activity, consistent with behaviours observed in Taar1-KO animals. In order to assess whether the effects of compound 22 are mediated through antagonism of TAAR1, experiments were carried out on Taar1-KO mice. Our results show that compound is also able to enhance amphetamine- and cocaine-mediated locomotor activity in Taar1-KO mice, suggesting that the in vivo effects of compound 22 are not mediated by TAAR1. In collaboration with Psychoactive Drug Screening Program at UNC-Chapel Hill, we attempted to determine the target for compound 22. PDSP results suggested several potential targets for compound 22. These include, the dopamine, norepinephrine and serotonin transporters; as well as sigma 1 and 2 receptors. Furthermore, the dopamine D2 receptor was also an initial hit in a functional assay performed by PDSP. Our follow-up studies using heterologous cell systems showed that neither DAT nor dopamine D2 dopamine receptors are targets of compound 22. Therefore, the biological target of compound 22 mediating its psychoactive effects remain unknown.
Source: TSpace (University of Toronto)
Author: Vincent Lam
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2776062791