Optimisation of imidazole compounds as selective TAAR1 agonists: Discovery of RO5073012

Galley, Guido; Stalder, Henri; Goergler, Annick; Hoener, Marius C.; Norcross, Roger D.

doi:10.1016/j.bmcl.2012.06.060

Cited by 55 publications

(40 citation statements)

References 14 publications

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“…This has been confirmed after expression of TAAR1 in a variety of cell types and with various approaches to analyze cAMP concentrations used (Reese et al, 2007;Wainscott et al, 2007;Barak et al, 2008;Hu et al, 2009;Espinoza et al, 2011;Revel et al, 2011;Liu et al, 2014). In fact, cAMP assays are now a central component of TAAR1 ligand screening programs (Bradaia et al, 2009;Revel et al, 2011Revel et al, , 2012aRevel et al, , 2013Stalder et al, 2011;Galley et al, 2012Galley et al, , 2015.…”

Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 82%

Trace Amines and Their Receptors

Gainetdinov¹,

Hoener²,

Berry³

2018

Pharmacol Rev

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Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 82%

Trace Amines and Their Receptors

Gainetdinov¹,

Hoener²,

Berry³

2018

Pharmacol Rev

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258

251

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“…Treatment with various selective TAAR 1 agonists (RO5166017, RO5203648, RO5256390, RO5073012 and RO5263397) dose-dependently inhibited cocaine- or NMDA antagonists L-687,414- or phencyclidine-induced hyperlocomotion in wild-type mice but not in Taar 1−/− mice (Galley et al, 2012; Revel et al, 2011; Revel et al, 2012b; Revel et al, 2013). Besides, RO5166017 and RO5203648 also attenuated hyperlocomotion in DAT −/− mice.…”

Section: Taar 1 Ligands and The Behavioral Pharmacology Of Drugs Ofmentioning

confidence: 98%

Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction

2015

European Journal of Pharmacology

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Abuse of and addiction to psychostimulants remains a challenging clinical issue, yet no effective pharmacotherapy is available. Trace amine associated receptor 1 (TAAR 1) is increasingly recognized as a novel drug target that participates in the modulation of drug abuse. This review analyzed existing preclinical evidence from electrophysiological, biochemical to behavioral aspects regarding the functional interactions between TAAR 1 and dopaminergic system. TAAR 1 knockout mice demonstrate increased sensitivity to dopaminergic activation while TAAR 1 agonists reduce the neurochemical effects of cocaine and amphetamines, attenuate abuse- and addiction-related behavioral effects of cocaine and methamphetamine. It is concluded that TAAR 1 activation functionally modulate the dopaminergic activity and TAAR 1 agonists appear to be promising pharmacotherapies against psychostimulant addiction.

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“…Interestingly, serotonin receptor antagonists such as cyproheptadine as well as adrenergic receptor antagonists such as phentolamine have been found to be TAAR1 agonists . Up to now, only a small number of selective TAAR1 agonists, such as RO5166017 , RO5073012 , RO5203648 , R05263397 , RO5256390 and T 1 AM are discussed in literature , while only one selective antagonist is actually known: N ‐(3‐Ethoxy‐phenyl)‐4‐pyrrolidin‐1‐yl‐3‐trifluoromethyl‐benzamide, EPPTB (Figure ) . This latest finding suggests that the TAAR1 ligand‐binding promiscuity might reflect the evolutionary link between TAAR and homologous vertebrate aminergic receptors or invertebrate tyramine receptors (TAR) and octopamine receptors (OAR) .…”

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confidence: 99%

Further Insights Into the Pharmacology of the Human Trace Amine‐Associated Receptors: Discovery of Novel Ligands for TAAR1 by a Virtual Screening Approach

et al. 2014

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Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor that is expressed in brain and periphery and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA), tyramine, tryptamine, octopamine. The receptor is known to have a very rich pharmacology and could be also activated by different classes of compounds, including dopaminergic, adrenergic and serotonergic ligands. It is expected that targeting hTAAR1 could provide a novel pharmacological approach for several human disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder, Parkinson's disease and metabolic diseases. Only recently, a small number of selective hTAAR1 agonists (among which RO5166017 and T1 AM) and antagonist (EPPTB), have been reported in literature. With the aim to identify new molecular entities able to act as ligands for this target, we used an homology model for the hTAAR1 and performed a virtual screening procedure on an in-house database of compounds. A number of interesting molecules were selected and by testing them in an in vitro assay we found several agonists and one antagonist, with activities in the low micromolar range. These compounds could represent the starting point for the development of more potent and selective TAAR1 ligands.

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Optimisation of imidazole compounds as selective TAAR1 agonists: Discovery of RO5073012

Cited by 55 publications

References 14 publications

Trace Amines and Their Receptors

Trace Amines and Their Receptors

Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction

Further Insights Into the Pharmacology of the Human Trace Amine‐Associated Receptors: Discovery of Novel Ligands for TAAR1 by a Virtual Screening Approach

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