• DOI:10.1124/jpet.106.112532
• Corpus ID: 10829497

Pharmacologic Characterization of the Cloned Human Trace Amine-Associated Receptor1 (TAAR1) and Evidence for Species Differences with the Rat TAAR1

@article{Wainscott2007PharmacologicCO,
  title={Pharmacologic Characterization of the Cloned Human Trace Amine-Associated Receptor1 (TAAR1) and Evidence for Species Differences with the Rat TAAR1},
  author={D Bradley Wainscott and Sheila P. Little and Tinggui Yin and Yuan-Kun Tu and Vincent Patrick Rocco and John Xiaoqiang He and David L. G. Nelson},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2007},
  volume={320},
  pages={475 - 485}
}

• D. B. Wainscott, S. Little, +4 authors D. Nelson
• Published 1 January 2007
• Biology, Chemistry
• Journal of Pharmacology and Experimental Therapeutics

The hemagglutinin-tagged human trace amine-associated receptor1 (TAAR1) was stably coexpressed with rat Gαs in the AV12-664 cell line, and receptor activation was measured as the stimulation of cAMP formation. After blockade of endogenously expressed α2- and β-adrenoceptors with 2-[2-(2-methoxy-1,4-benzodioxanyl)]-imidazoline hydrochloride (2-methoxyidazoxan, RX821002) and alprenolol, respectively, the resulting pharmacology was consistent with that of a unique receptor subtype. β-Phenylethylamine (β-PEA), the putative endogenous ligand, gave an EC50 of 106 ± 5 nM in the assay. For a series of β-PEA analogs used to explore the pharmacophore, small substituents at ring positions 3 and/or 4 generally resulted in compounds having lower potency than β-PEA, although several were as potent as β-PEA. However, small substituents at ring position 2 resulted in a number of compounds having potencies as good as or better than β-PEA. A number of nonselective antagonists known to share affinity for multiple monoaminergic receptors were evaluated for their ability to inhibit β-PEA stimulation of the human TAAR1. None had an IC50 <10 μM. For comparison, the rat TAAR1 receptor was expressed in the AV12-664 cell line. A number of agonist compounds had significantly different relative potencies between the rat and human TAAR1, demonstrating a significant species difference between the rat and human TAAR1. The TAAR1 receptor exhibits a pharmacologic profile uniquely different from those of classic monoaminergic receptors, consistent with the structural information that places them in a distinct family of receptors. This unique pharmacologic profile suggests the potential for development of TAAR-selective agonists and antagonists to study their physiologic roles.