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The Discovery of Novel TAAR1 Ligands through the use of a Homology Model and in silico Screening

Trace amines (TA) are by‐products of the synthesis of classical neurotransmitters within the brain. TA's exert their effect by activating a class of GPCRs including, trace amine associated receptor 1 (TAAR1) where TAAR1 signalling has been shown to be a negative regulator of dopamine transmission. In this study, we aimed to identify novel selective TAAR1 compounds for TAAR1 for in vivo testing. To this end, a TAAR1 homology model was generated and an in silico screen of 3 million commercially available compounds was conducted. The top 42 compounds, based on predicted affinities, were ordered and screened for TAAR1 activity using a cAMP BRET biosensor. From the 42 compounds tested, a mix of antagonists (seven compounds) and agonists (nine compounds) were found, yielding an initial hit rate of 35%. Of the nine identified agonists, three compounds (8, 16, and 25) displayed high potency for TAAR1 with EC50 values of 18, 1.0, and 52 µM respectively. In order to identify compounds with improved affinity for TAAR1, five analogs of compounds 8 and 16 were tested. Of the five analogs of compound 8 tested, only one compound (8b) displayed agonist activity with no improvements on efficacy or potency compared to compound 8. Two of the five compound 16 analogs (16a and 16b) had a left shift of ~10 fold in their EC50 for activation of cAMP signalling by TAAR. Furthermore the analog 16b had higher efficacy for TAAR1 activation than compound 16. In conclusion we have discovered three unique novel partial TAAR1 agonists with new chemical backbones where compound 16 and its analogs had the most optimal pharmacological profile. The in vivo effects as well as identification of higher affinity analogs of these compounds will be undertaken in the future.