A Decade of Pharma Discovery Delivers New Tools Targeting Trace Amine-Associated Receptor 1

Tallman, Katie R.; Grandy, David K.

doi:10.1038/npp.2012.148

Cited by 7 publications

(5 citation statements)

References 9 publications

(15 reference statements)

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“…If a compound acts at multiple targets which in turn leads to the release or accumulation of additional neurotransmitters, the response becomes even more difficult to trace back to the initial drug treatment. This could be the case for the amphetamines, which act at transporters to raise biogenic amine levels and also have high affinity for biogenic amine receptors [35,36,37]. If the transporter is affected, then the levels of neurotransmitters will be modulated and this combined effect reveals a ‘unique’ behavioral response that is not entirely due to an altered activation of the receptor that is in question.…”

Section: Specific Challenges In Studying Functional Selectivity In Vivomentioning

confidence: 99%

Functional selectivity of GPCR signaling in animals

Zhou

Bohn

2014

Current Opinion in Cell Biology

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At one time, G protein-coupled receptors were envisioned to simply relay either inhibitory or stimulatory binary signals through engaging particular G proteins. These receptors are now viewed as complex, multidimensional triggers of a variety of potential signaling cascades. This review will showcase current attempts to elucidate biased signaling and functional selectivity in tissues and organs as well as in the whole animal. In addition, it will emphasize the challenges that are inherent in attributing bias in a living system as well as offer opinions as to the manner in which these problems may be approached.

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Section: Specific Challenges In Studying Functional Selectivity In Vivomentioning

confidence: 99%

Functional selectivity of GPCR signaling in animals

Zhou

Bohn

2014

Current Opinion in Cell Biology

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“…10,11 With its expression in midbrain dopamine neurons 1,2,12−15 and the pancreas 2 and interesting structure−activity profile, 2,4−6 TAAR1 has begun to receive attention from the pharmaceutical industry as a target for new medication development. 16 Already one of these programs has identified a selective antagonist, 13 a partial agonist, 15 and a selective full agonist, 14 the latter having recently been shown to reduce cocaine self-administration in rats. While little has been published regarding how these ligands physically interact with TAAR1, 17−19 the recent modeling study by Cichero et al 18 identified residues including the conserved D103 in human TAAR1 (hTAAR1) (D102 in mouse TAAR1 (mTAAR1) and rat TAAR1 (rTAAR1)) likely involved in ligand binding.…”

Section: ■ Introductionmentioning

confidence: 99%

“…With its expression in midbrain dopamine neurons ,,− and the pancreas and interesting structure–activity profile, ,− TAAR1 has begun to receive attention from the pharmaceutical industry as a target for new medication development . Already one of these programs has identified a selective antagonist, a partial agonist, and a selective full agonist, the latter having recently been shown to reduce cocaine self-administration in rats.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Determinants of Trace Amine-Associated Receptor 1’s Functional Selectivity for the Stereoisomers of Amphetamine and Methamphetamine

et al. 2014

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Amphetamines are widely abused drugs that interfere with dopamine transport and storage. Recently, however, another mechanism of action was identified: stereoselective activation of the GαS protein-coupled trace amine-associated receptor 1 (TAAR1). To identify structural determinants of this stereoselectivity, we functionally evaluated six mutant receptors in vitro and then used homology modeling and dynamic simulation to predict drug affinities. Converting Asp102 to Ala rendered mouse and rat TAAR1 (mTAAR1 and rTAAR1, respectively) insensitive to β-phenylethylamine, amphetamine (AMPH), and methamphetamine (METH). Mutating Met268 in rTAAR1 to Thr shifted the concentration-response profiles for AMPH and METH isomers rightward an order of magnitude, whereas replacing Thr268 with Met in mTAAR1 resulted in profiles leftward shifted 10-30-fold. Replacing Asn287 with Tyr in rTAAR1 produced a mouselike receptor, while the reciprocal mTAAR1 mutant was rTAAR1-like. These results confirm TAAR1 is an AMPH/METH receptor in vitro and establish residues 102 (3.32) and 268 (6.55) as major contributors to AMPH/METH binding with residue 287 (7.39) determining species stereoselectivity.

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“…However, poor solubility and brain-blood barrier penetration of this compound gives the possibility to investigate only in vitro effects of TAAR antagonism [8]. To advance pharmacological innovation, two groups attempted to discover the molecular determinants responsible for ligand-receptor interaction for TAAR1 [62][63][64]. For this purpose, our group developed a theoretical model of the human TAAR1 developed by homology modeling and made docking studies with known TAAR1 agonists finding important amino acid residues for the activity of these ligands [63].…”

Section: S Espinoza and Rr Gainetdinovmentioning

confidence: 99%

Neuronal Functions and Emerging Pharmacology of TAAR1

Espinoza

Gainetdinov

2014

Topics in Medicinal Chemistry

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Trace amine-associated receptor 1 (TAAR1) is a member of TAAR family of G protein-coupled receptors (GPCRs). The members of this class of receptors discovered in 2001 have been found in some tissues ranging from the central nervous system to the olfactory epithelium and in some peripheral organs. The best studied receptor, TAAR1, is activated by a class of compounds named trace amines (TAs) that include compounds such as β-phenylethylamine (PEA), p-tyramine, octopamine, and tryptamine normally present at low levels in the mammalian brain. Although TA levels have been associated with many neuropsychiatric disorders, only the discovery of TAAR1 validated their physiological role. TAAR1 can modulate monoamine neurotransmission and, in particular, dopamine systems. Several studies have demonstrated that TAAR1 knockout (TAAR1-KO) mice display a supersensitive dopaminergic system, while activation of TAAR1 can reduce dopaminergic hyperactivity obtained either with pharmacological tools or present in genetic mouse model. For these reasons, TAAR1 has been proposed as a novel therapeutic target for neuropsychiatric disorders such as schizophrenia, bipolar disorder, and addiction. Moreover, several peripheral functions of TAAR1 have been described recently indicating intriguing novel TAAR1 roles in system physiology. Here we will review brain and peripheral functions mediated by TAAR1 and other TAARs.

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A Decade of Pharma Discovery Delivers New Tools Targeting Trace Amine-Associated Receptor 1

Cited by 7 publications

References 9 publications

Functional selectivity of GPCR signaling in animals

Functional selectivity of GPCR signaling in animals

Exploring the Determinants of Trace Amine-Associated Receptor 1’s Functional Selectivity for the Stereoisomers of Amphetamine and Methamphetamine

Neuronal Functions and Emerging Pharmacology of TAAR1

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