Abstract
Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.
Highlights
Trace amines are a class of endogenous chemicals present at low levels in the body, both in the periphery and the brain of vertebrates, including mammals [1]
Except for TAAR1, all the other trace amine-associated receptors (TAARs) are expressed in the olfactory epithelium and form a new class of olfactory receptors that sense volatile amines involved in innate behaviours [5]
TAAR1 has become a promising target for pharmacotherapy, and recent clinical trials suggest a potential use for schizophrenia of TAAR1 agonists with a new mechanism of action not involving blockade of D2 dopamine receptors [15]
Summary
Trace amines are a class of endogenous chemicals present at low levels in the body, both in the periphery and the brain of vertebrates, including mammals [1]. Initial studies showed the expression of TAAR1 and other TAARs in some human and rodent brain regions. TAAR1 is the most studied member of the family and is activated by trace amines and by amphetamines and other psychotropic compounds [3] It modulates the dopamine system by influencing D2 dopamine receptor activity and the firing of dopaminergic neurons [6–11]. TAAR5 seems to modulate the serotonin system since TAAR5-KO mice have altered serotonin levels in different brain regions and enhanced functions of the 5-HT1A receptor [16]. These mutants display somewhat elevated dopamine levels and increased adult neurogenesis in the subventricular and subgranular zones [20]. Scheme predictive tools. of the applied screening protocol followed by biological assays and in silico ADME predictive tools
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