Behavioral Effects of a Potential Novel TAAR1 Antagonist

Abstract

The trace amine associated receptor 1 (TAAR1) is a G-protein coupled receptor expressed in the monoaminergic regions of the brain, and represents a potential novel therapeutic target for the treatment of neurological disorders. While selective agonists for TAAR1 have been successfully identified, only one high affinity TAAR1 antagonist has been described thus far. We previously identified four potential low potency TAAR1 antagonists through an <i>in silico</i> screen on a TAAR1 homology model. One of the identified antagonists (compound <b>22</b>) was predicted to have favorable physicochemical properties, which would allow the drug to cross the blood brain barrier. <i>In vivo</i> studies were therefore carried out and showed that compound <b>22</b> potentiates amphetamine- and cocaine-mediated locomotor activity. Furthermore, electrophysiology experiments demonstrated that compound <b>22</b> increased firing of dopamine neurons similar to EPPTB, the only known TAAR1 antagonist. In order to assess whether the effects of compound <b>22</b> were mediated through TAAR1, experiments were carried out on TAAR1-KO mice. The results showed that compound <b>22</b> is able to enhance amphetamine- and cocaine-mediated locomotor activity, even in TAAR1-KO mice, suggesting that the <i>in vivo</i> effects of this compound are not mediated by TAAR1. In collaboration with Psychoactive Drug Screening Program, we attempted to determine the targets for compound <b>22</b>. Psychoactive Drug Screening Program (PDSP) results suggested several potential targets for compound <b>22</b> including, the dopamine, norepinephrine and serotonin transporters; as well as sigma 1 and 2 receptors. Our follow-up studies using heterologous cell systems showed that the dopamine transporter is not a target of compound <b>22</b>. Therefore, the biological target of compound <b>22</b> mediating its psychoactive effects still remains unknown.