Trace Amine Family Related Drug Discovery Products
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In order to separate a group of endogenous vertebrate monoamines from their more prevalent close structural relatives, the catecholamine and indoleamine neurotransmitters, the term "trace amine" itself appears to have been developed. The term "trace" was initially used to underline the low endogenous tissue concentrations, which are at least 100 times lower than those of the equivalent neurotransmitters. The term "trace amine" later came to refer to only a small subset of endogenous monoamines, particularly β-phenylethylamine (PEA), ρ-tyramine (TYR), tryptamine (TRP), and ρ-octopamine (OCT), the substances that bear the most striking structural resemblance to the well-known monoamine neurotransmitters and were the main motivation for much of the prereceptor research.
Fig.1. Traditional trace amines. (Gainetdinov, 2018)
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Overview of Trace Amine Family
TAARs are not phylogenetically connected to canonical odorant receptors (ORs) or other chemosensory receptors, but are distantly related to biogenic amine receptors. Studies in rodent, monkey, and fish have shown that all TAARs, with the exception of TAAR1, serve as olfactory receptors. The olfactory system has a substantially enhanced TAAR expression. In the nose, TAARs exhibit the distinctive features of OR expression, including dispersion within a spatial zone and restriction to sparse sensory neurons. Additionally, the neonatal Grueneberg ganglion expresses TAARs.
TAAR proteins are found in sensory neurons and are localized to axons and olfactory cilia, which are the sites of odor sensing and axon guidance, respectively. Due to the expression of Gaolf and other conventional olfactory signaling molecules in TAAR neurons, TAARs and ORs most likely use comparable intracellular pathways. Additionally, in heterologous cells, activated TAARs couple to cAMP pathways, and pharmacological inhibition of adenylyl cyclase prevents TAAR neurons from responding to odors.
Fig.2. The mammalian TAAR phylogeny. (Liberles, 2015)
Trace Amine Family Drug Discovery
As the TAAR repertoire changes across the phylogeny, it offers a dynamic environment for the study of sensory biology. Numerous TAARs are capable of detecting volatile and unpleasant amines, however the olfactory system can ignore ligand- or function-based limitations on TAAR development. Some TAARs have undergone mutations to identify novel ligands, and nearly the whole teleost clade has lost the traditional amine-recognition pattern. Additionally, while some TAARs can sense unpleasant odors, other species may exhibit different TAAR-mediated behaviors. It's possible that the enormous flexibility of the olfactory system development allows for functional modifications in the TAAR family that are exclusive to a given lineage. An attractive opportunity for the mechanical unraveling of odor valence encoding is presented by the capacity of specific TAARs to mediate aversion and attraction behavior.
References
- Gainetdinov, R.R.; et al. Trace amines and their receptors. Pharmacological reviews. 2018, 70(3): 549-620.
- Liberles, S.D. Trace amine-associated receptors: ligands, neural circuits, and behaviors. Current opinion in neurobiology. 2015, 34: 1-7.
