Journal
PHARMACOLOGY & THERAPEUTICS
Volume 116, Issue 3, Pages 355-390Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2007.06.007
Keywords
noncatecholic phenylethylamines; trace amine; phenethylamine; tyramine; iodothyronamine; orphan receptor; psychostimulant; schizophrenia; mental health
Categories
Funding
- NIDA NIH HHS [R01 DA012062-05, R01 DA008562-07, R01 DA010703-03] Funding Source: Medline
- NIMH NIH HHS [R01 MH067497, R01 MH067497-05] Funding Source: Medline
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Interest has recently been rekindled in receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the trace amines (TA) beta-phenylethylamine (PEA), tyramine (TYR), octopamine. (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of 2 publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers Borowsky et al. as TA1 and Bunzow et al. as TA receptor 1 (TAR1). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines, recombinant rodent and human TAR dose-dependently couple to the stimulation of adenosine 3',5'-monophosphate (cAMP) production. Structure-activity profiling based on this functional response has revealed that in addition to the TA, other biologically active compounds containing a 2-carbon aliphatic side chain linking an amino group to at least 1 benzene ring are potent and efficacious TA receptor agonists with amphetamine (AMPH), methamphetamine, 3-iodothyronamine, thyronamine, and dopamine (DA) among the most notable. Almost 100 years after the search for TAR began, numerous TA1/TAR1-related sequences, now called TA-associated receptors (TAAR), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TAR, a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCR. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast. (C) 2007 Elsevier Inc. All rights reserved.
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