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}
}
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… Expand
Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study.
TLDR
Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM, and selected diphenylmethane analogues, namely 1 and 2, showed potent functional activity in in vitro and in vivo models. Expand
Human and mouse trace amine-associated receptor 1 have distinct pharmacology towards endogenous monoamines and imidazoline receptor ligands.
TLDR
The successful expression of human and mouse TAAR1 and the characterization of their responses to various natural and synthetic agonists raise new possibilities about the mechanism of some of the imidazoline-related agents. Expand
Trace amine-associated receptor 1-Family archetype or iconoclast?
  • D. Grandy
  • Biology, Medicine
  • Pharmacology & therapeutics
  • 2007
TLDR
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. Expand
Exploring the determinants of trace amine-associated receptor 1's functional selectivity for the stereoisomers of amphetamine and methamphetamine.
TLDR
These results confirm TAAR1 is an AMPH/METH receptor in vitro and establish residues 102 and 268 as major contributors to AMPH-METH binding with residue 287 determining species stereoselectivity. Expand
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TLDR
Key, nonconserved specificity determinant residues in transmembranes helices 4 and 7 within the ligand binding site appear to be the primary source of a number of the observed ligand preferences. Expand
Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class.
TLDR
The observed parallel between hTAAR1 and rhTAar1 responses supports the rhesus monkey as a highly translational model for developing novel TAAR1-directed compounds as therapeutics for amphetamine-related addictions. Expand
Amphetamines Activate G-Protein Coupled Trace Amine-Associated Receptor 1 (TAAR1)
Abstract Trace amine-associated receptor 1 (TAAR1) shares significant nucleotide and amino acid sequence identity with dopamine, adrenergic, and serotonergic receptors. Heterologously expressed inExpand
Trace Amine-Associated Receptor 1 Displays Species-Dependent Stereoselectivity for Isomers of Methamphetamine, Amphetamine, and Para-Hydroxyamphetamine
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In response to METH, AMPH, or POHA exposure, the accumulation of cAMP by HEK-293 cells stably expressing different species of TAar1 was concentration- and isomer-dependent, suggesting that, in vivo, TAAR1 could be a novel mediator of the effects of these drugs. Expand
Inverse Agonistic Action of 3-Iodothyronamine at the Human Trace Amine-Associated Receptor 5
TLDR
The data suggest that the human TAAR5 is a target for 3-T1AM, exhibiting inhibitory effects on IP3 formation and MAP kinase signaling pathways, but does not mediate Gs signaling effects as observed for TAAR1. Expand
Toward deciphering the code to aminergic G protein-coupled receptor drug design.
TLDR
This work rationally designed and synthesized rat TAAR(1) superagonists and lead antagonists using the rotamer toggle switch model of aminergic GPCR activation to provide a conceptual model for understanding the relationship between the molecular structure of a drug and its pharmacological properties. Expand
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