Elsevier

Pharmacology & Therapeutics

Volume 180, December 2017, Pages 161-180
Pharmacology & Therapeutics

Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges

https://doi.org/10.1016/j.pharmthera.2017.07.002Get rights and content
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Abstract

The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5 years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.

Abbreviations

2-AI
2-aminoindane
2C-B
2,5-dimethoxy-4-bromophenethylamine
5-IAI
5-iodo-2-aminoindane
COMT
catechol-O-methyl transferase
CPP
conditioned place preference
DAT
dopamine transporter
DIO
diet-induced obese
DMT
N,N-dimethyltryptamine
EAAT2
excitatory amino acid transporter 2
EPPTB
N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide (RO5212773)
FMO3
flavin-containing monooxygenase 3
GirK
G protein-coupled inwardly-rectifying potassium
GLP-1
glucagon like peptide 1
GPCR
G protein-coupled receptor
IUPHAR
International Union of Basic and Clinical Pharmacology
LSD
lysergic acid diethylamide
m-CPP
m-chlorophenylpiperazine
MDMA
3,4-methylenedioxymethamphetamine
NC-IUPHAR
International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification
PANSS
positive and negative symptom scale
phMRI
pharmacological magnetic resonance imaging
SNpc
substantia nigra pars compacta
TAAR
trace amine-associated receptor
VTA
ventral tegmental area

Keywords

Trace amine-associated receptors
Schizophrenia
Addiction
Metabolic disorders
Immune system, Microbiota

Cited by (0)

All authors contributed equally to this manuscript.