Trends in Pharmacological Sciences
A renaissance in trace amines inspired by a novel GPCR family
Section snippets
Trace amines find their receptors
The classical biogenic amines [serotonin (5-HT), noradrenaline, adrenaline, dopamine and histamine] have important roles as neurotransmitters in the central and peripheral nervous systems [1]. Their synthesis and storage, in addition to their degradation and reuptake after release, are tightly regulated, and an imbalance in the levels of biogenic amines is known to be responsible for altered brain function in many pathological conditions 2, 3, 4, 5. A second class of endogenous amine compounds,
Molecular properties of trace amine-associated receptors
All mammalian TAARs analyzed to date share several molecular properties [15]. All except one TAAR gene [TAAR2 (GPR58)] are single-exon encoded, locate to a narrow region of ∼100–200 kb of a single chromosome and have coding sequences of ∼1 kb in length. The total number of genes and the proportion of intact genes compared with the proportion of pseudogenes differ substantially between species: there are 19 (including 2 pseudogenes) and 16 (including 1 pseudogene) TAAR genes in rat and mouse
Trace amine metabolism and pharmacology
TAs (β-PEA, p-tyramine, octopamine and tryptamine) are all primary amines generated directly by enzymatic decarboxylation of their respective precursor amino acids or, in the case of octopamine, via additional conversion by dopamine β-hydroxylase (DBH) (Figure 2). TAs are metabolized to biologically inactive degradation products predominantly via monoamine oxidase (MAO) with different selectivities for the MAO-A or MAO-B subtype. As a result of the rapid turnover rate of TAs, the endogenous
TAARs as potential drug targets for the treatment of psychiatric disorders
The dysregulation of TA levels has been linked to several diseases, which highlights the corresponding members of the TAAR family as potential targets for drug development. In this article, we focus on the relevance of TAs and their receptors to nervous system-related disorders, namely schizophrenia and depression; however, TAs have also been linked to other diseases such as migraine, attention deficit hyperactivity disorder, substance abuse and eating disorders 7, 8, 36.
Clinical studies report
Outlook and future perspectives
The identification of specific receptors has always been key to the understanding of the biological function and pharmacology of any transmitter-like biological compound, as the example of histamine illustrates well: when the importance of amine-mediated systems emerged in the 1960s, it was only after the identification of specific receptors that histamine was generally accepted as an established neurotransmitter 56, 57. Likewise, it is only the recent identification of TAARs, some of which
Acknowledgements
We would like to thank our colleagues M. Ebeling, N.A. Kratochwil, J-L. Moreau, H. Stalder, S. Kolczewski, E. Borroni, J.G. Wettstein, A.J. Sleight and D.K. Grandy for many stimulating discussions. We acknowledge the continued support by F. Hoffmann-La Roche.
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