A renaissance in trace amines inspired by a novel GPCR family

Lindemann, Lothar; Hoener, Marius C.

doi:10.1016/j.tips.2005.03.007

Cited by 247 publications

(187 citation statements)

References 55 publications

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“…In addition, the similarity analysis was able to predict receptor pharmacologies not apparent from the phylogenetic analysis of the trace amine-associated receptor family. 45,46 This is attributable both to a reduction of noise achieved by focusing on the LPV and to the use of a pharmacophorebased metric in the similarity analysis presented here.…”

Section: Discussionmentioning

confidence: 99%

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Kratochwil

Malherbe

Lindemann

et al. 2005

J. Chem. Inf. Model.

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G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Here, a comprehensive and automated method allowing fast analysis and comparison of these putative binding pockets across the entire GPCR family is presented. The method relies on a robust alignment algorithm based on conservation indices, focusing on pharmacophore-like relationships between amino acids. Analysis of conservation patterns across the GPCR family and alignment to the rhodopsin X-ray structure allows the extraction of the amino acids lining the TM binding pocket in a so-called ligand binding pocket vector (LPV). In a second step, LPVs are translated to simple 3D receptor pharmacophore models, where each amino acid is represented by a single spherical pharmacophore feature and all atomic detail is omitted. Applications of the method include the assessment of selectivity issues, support of mutagenesis studies, and the derivation of rules for focused screening to identify chemical starting points in early drug discovery projects. Because of the coarseness of this 3D receptor pharmacophore model, however, meaningful scoring and ranking procedures of large sets of molecules are not justified. The LPV analysis of the trace amine-associated receptor family and its experimental validation is discussed as an example. The value of the 3D receptor model is demonstrated for a class C GPCR family, the metabotropic glutamate receptors.

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Section: Discussionmentioning

confidence: 99%

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Kratochwil

Malherbe

Lindemann

et al. 2005

J. Chem. Inf. Model.

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“…27−29 In summary, we report here the discovery and optimization of 2-aminooxazolines as novel, selective, full and partial TAAR1 agonists. Starting from the known adrenergic ligand S18616 (1) and modifying the linker region and exploring additional SAR, we investigated several subseries of TAAR1 ligands. Besides functional activity at hTAAR1 and selectivity vs adrenergic α 2A receptor, metabolic stability measured in hepatocytes was used as a key parameter to finally select two molecules, 18 (RO5256390) and 48 (RO5263397), for further studies.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

Galley

Beurier

Décoret

et al. 2016

ACS Med. Chem. Lett.

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2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction. KEYWORDS: TAAR1 agonist, 2-aminooxazoline, SAR, schizophrenia T race amines (TAs) are metabolites of amino acids with structural similarity to biogenic amines and represent the endogenous ligands of the trace amine associated receptor 1 (TAAR1). 1,2 Dysregulation of TAs in the brain has been linked to a variety of psychiatric diseases and selective TAAR1 ligands have gained much interest as potential therapeutics for depression, schizophrenia, bipolar disorder, ADHD, and psychostimulant addiction. 3 The modulatory role of this G protein-coupled receptor on monoaminergic neurotransmission has recently been investigated and confirmed by characterization of a transgenic mouse line overexpressing TAAR1 in central nervous system neurons. 4 Further efforts were made to identify potent and selective TAAR1 agonists with favorable pharmacokinetic properties in order to prove the modulatory effect on dopaminergic signaling in vivo. 5 In an endeavor to discover a novel and selective TAAR1 chemotype, we considered application of the SOSA approach (Selective Optimization of Side Activities) to adrenergic ligands as a viable lead identification strategy. 6 Structural similarity of TAAR1 agonists with adrenergic agonists was already known from our previous work 5 pointing toward a similarity of the binding regions of both receptors. 7,8 Therefore, we searched the literature and in-house databases for adrenergic ligands reported as drugs or development candidates, whereupon the alpha 2 adrenergic receptor partial agonist S18616 from Servier (1) caught our attention. 9 Pleasingly, testing this candidate revealed (besides its expected activity at the human α 2A receptor) a high functional activity at human TAAR1 (EC 50 = 15 nM). 10 A medicinal chemistry optimization program was then started aiming for compounds selective for TAAR1, where the known TAAR1 pharmacophore motif (aromatic moiety linked to a basic headgroup) of S18616 was kept, but the linker region was modified by opening the central six-membered ring (Figure 1). For all such derived compounds selectivity data was obtained by measuring functional activity at the human TAAR1 receptor (EC 50 hTAAR1) and in addition at the human adrenergic α 2A receptor (hα 2A ) (Table 1).All 2-aminooxazolines were synthesized from the corresponding amino alcohols 15 and cyanogen bromide in the presence of a base as depicted in Scheme 1. The enantiomerically pure amino alcohols were obtained from the chiral pool (e.g., via reduction of amino acids or their derivatives). The procedures are describ...

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“…Because of their structural similarity to classical biogenic amines, TAs were for a long time believed to modulate neurotransmission by displacing biogenic amines from vesicular stores or by acting on transporters in an amphetamine-like manner. It was not until TAs were found to bind to members of a family of GPCRs, the TAassociated receptors (TAARs), that receptor-mediated mechanisms were evoked (2)(3)(4)(5). While several TAARs were identified, only TAAR1 and, to a lesser extent, TAAR4 respond to typical TAs (5).…”

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confidence: 99%

“…It was not until TAs were found to bind to members of a family of GPCRs, the TAassociated receptors (TAARs), that receptor-mediated mechanisms were evoked (2)(3)(4)(5). While several TAARs were identified, only TAAR1 and, to a lesser extent, TAAR4 respond to typical TAs (5). TAs such as p-tyr and ␤-phenylethylamine activate human, mouse, and rat TAAR1 with EC 50 values of 0.2-1.7 M. Other TAs (octopamine, tryptamine), classical biogenic amines, and amphetamine-related psychostimulants have much reduced potency and efficacy at TAAR1.…”

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confidence: 99%

“…Taar1 knockout mice also display behavioral and neurochemical signs of DA supersensitivity, a feature thought to relate to positive symptoms of schizophrenia (8). In addition, TAs were implicated in the etiology of depression, addiction, attention-deficit/ hyperactivity disorder, and Parkinson's disease (5,9,10). However, validation of therapeutic concepts was hampered by the lack of a ligand that specifically regulates TAAR1 activity in vivo.…”

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The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system

Bradaı̈a

Trube

Stalder

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) that is nonselectively activated by endogenous metabolites of amino acids. TAAR1 is considered a promising drug target for the treatment of psychiatric and neurodegenerative disorders. However, no selective ligand to identify TAAR1-specific signaling mechanisms is available yet. Here we report a selective TAAR1 antagonist, EPPTB, and characterize its physiological effects at dopamine (DA) neurons of the ventral tegmental area (VTA). We show that EPPTB prevents the reduction of the firing frequency of DA neurons induced by p-tyramine (p-tyr), a nonselective TAAR1 agonist. When applied alone, EPPTB increases the firing frequency of DA neurons, suggesting that TAAR1 either exhibits constitutive activity or is tonically activated by ambient levels of endogenous agonist(s). We further show that EPPTB blocks the TAAR1-mediated activation of an inwardly rectifying K ؉ current. When applied alone, EPPTB induces an apparent inward current, suggesting the closure of tonically activated K ؉ channels. Importantly, these EPPTB effects were absent in Taar1 knockout mice, ruling out off-target effects. We additionally found that both the acute application of EPPTB and the constitutive genetic lack of TAAR1 increase the potency of DA at D2 receptors in DA neurons. In summary, our data support that TAAR1 tonically activates inwardly rectifying K ؉ channels, which reduces the basal firing frequency of DA neurons in the VTA. We hypothesize that the EPPTB-induced increase in the potency of DA at D2 receptors is part of a homeostatic feedback mechanism compensating for the lack of inhibitory TAAR1 tone.desensitization ͉ dopamine supersensitivity ͉ Kir3 ͉ trace amines ͉ VTA T race amines (TAs) such as p-tyr, ␤-phenylethylamine, octopamine, and tryptamine are metabolites of amino acids that are found at low concentrations in the brain (1). Because of their structural similarity to classical biogenic amines, TAs were for a long time believed to modulate neurotransmission by displacing biogenic amines from vesicular stores or by acting on transporters in an amphetamine-like manner. It was not until TAs were found to bind to members of a family of GPCRs, the TAassociated receptors (TAARs), that receptor-mediated mechanisms were evoked (2-5). While several TAARs were identified, only TAAR1 and, to a lesser extent, TAAR4 respond to typical TAs (5). TAs such as p-tyr and ␤-phenylethylamine activate human, mouse, and rat TAAR1 with EC 50 values of 0.2-1.7 M. Other TAs (octopamine, tryptamine), classical biogenic amines, and amphetamine-related psychostimulants have much reduced potency and efficacy at TAAR1.TA binding to TAAR1 engages G s -type G proteins that activate adenylyl cyclases (1). However, because TAs not only activate TAAR1 but also influence the activity of TAAR4, DA transporters, adrenergic, as well as serotonin receptors it was difficult to assign specific physiological functions to TAAR1 (1, 6). With the availability of Taar1 knockout mice (7,8) ...

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A renaissance in trace amines inspired by a novel GPCR family

Cited by 247 publications

References 55 publications

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system

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