Roger D Norcross

Publications (12)74.26 Total impact

• Article: Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine.

  Florent G Revel, Claas A Meyer, Amyaouch Bradaia, Karine Jeanneau, Eleonora Calcagno, Cédric B André, Markus Haenggi, Marie-Thérèse Miss, Guido Galley, Roger D Norcross, Roberto W Invernizzi, Joseph G Wettstein, Jean-Luc Moreau, Marius C Hoener
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  ABSTRACT: Trace amines (TAs) such as β-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).
  Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2012; 37(12):2580-92. · 6.99 Impact Factor
• Article: Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012.

  Guido Galley, Henri Stalder, Annick Goergler, Marius C Hoener, Roger D Norcross
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  ABSTRACT: A series of imidazole compounds has been identified which affords potent and selective partial and full agonists of the TAAR1 receptor. Starting from 2-benzyl-imidazoline screening hits, a series of structurally related 2-benzyl- and 4-benzyl-imidazoles was investigated first, but it proved highly challenging to obtain compounds having sufficient selectivity against the adrenergic alpha 2 receptor. This issue could be successfully addressed by modification of the linker region and SAR exploration led to the discovery of highly selective isopropyl-substituted 4-aminomethyl-imidazole compounds. The work culminated in the identification of the selective TAAR1 partial agonist RO5073012 (4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine, 24), which has a good pharmacokinetic profile after oral administration in rodents. RO5073012 has been found to be active in a behavioural rat model which is considered indicative for schizophrenia.
  Bioorganic & medicinal chemistry letters 06/2012; 22(16):5244-8. · 2.65 Impact Factor
• Article: Trace Amine-Associated Receptor 1 Partial Agonism Reveals Novel Paradigm for Neuropsychiatric Therapeutics.

  Florent G Revel, Jean-Luc Moreau, Raul R Gainetdinov, Antonio Ferragud, Clara Velázquez-Sánchez, Tatyana D Sotnikova, Stephen R Morairty, Anja Harmeier, Katrin Groebke Zbinden, Roger D Norcross, Amyaouch Bradaia, Thomas S Kilduff, Barbara Biemans, Bruno Pouzet, Marc G Caron, Juan J Canales, Tanya L Wallace, Joseph G Wettstein, Marius C Hoener
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  ABSTRACT: BACKGROUND: Trace amines, compounds structurally related to classical biogenic amines, represent endogenous ligands of the trace amine-associated receptor 1 (TAAR1). Because trace amines also influence the activity of other targets, selective ligands are needed for the elucidation of TAAR1 function. Here we report on the identification and characterization of the first selective and potent TAAR1 partial agonist. METHODS: The TAAR1 partial agonist RO5203648 was evaluated for its binding affinity and functional activity at rodent and primate TAAR1 receptors stably expressed in HEK293 cells, for its physicochemical and pharmacokinetic properties, for its effects on the firing frequency of monoaminergic neurons ex vivo, and for its properties in vivo with genetic and pharmacological models of central nervous system disorders. RESULTS: RO5203648 showed high affinity and potency at TAAR1, high selectivity versus other targets, and favorable pharmacokinetic properties. In mouse brain slices, RO5203648 increased the firing frequency of dopaminergic and serotonergic neurons in the ventral tegmental area and the dorsal raphe nucleus, respectively. In various behavioral paradigms in rodents and monkeys, RO5203648 demonstrated clear antipsychotic- and antidepressant-like activities as well as potential anxiolytic-like properties. Furthermore, it attenuated drug-taking behavior and was highly effective in promoting attention, cognitive performance, and wakefulness. CONCLUSIONS: With the first potent and selective TAAR1 partial agonist, RO5203648, we show that TAAR1 is implicated in a broad range of relevant physiological, behavioral, and cognitive neuropsychiatric dimensions. Collectively, these data uncover important neuromodulatory roles for TAAR1 and suggest that agonists at this receptor might have therapeutic potential in one or more neuropsychiatric domains.
  Biological psychiatry 06/2012; · 8.93 Impact Factor
• Article: Selective antagonists of mouse trace amine-associated receptor 1 (mTAAR1): discovery of EPPTB (RO5212773).

  Henri Stalder, Marius C Hoener, Roger D Norcross
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  ABSTRACT: High throughput screening of the Roche compound library identified benzanilides such as 1 and 2 as antagonists of TAAR1. Optimisation of this hit series led to the first selective TAAR1 antagonist (N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide EPPTB (RO5212773, 9f) having IC(50) of 28 nM at mouse TAAR1.
  Bioorganic & medicinal chemistry letters 02/2011; 21(4):1227-31. · 2.65 Impact Factor
• Article: Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors.

  Emmanuel Pinard, Daniela Alberati, Markus Bender, Edilio Borroni, Virginie Brom, Serge Burner, Holger Fischer, Dominik Hainzl, Remy Halm, Nicole Hauser, [......], Judith Lengyel, Hans-Peter Marty, Thierry Meyer, Jean-Luc Moreau, Roland Mory, Robert Narquizian, Roger D Norcross, Philipp Schmid, Roger Wermuth, Daniel Zimmerli
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  ABSTRACT: Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.
  Bioorganic & medicinal chemistry letters 10/2010; 20(23):6960-5. · 2.65 Impact Factor
• Article: 4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.

  Adrian Wai-Hing Cheung, John Brinkman, Fariborz Firooznia, Alexander Flohr, Joseph Grimsby, Mary Lou Gubler, Kevin Guertin, Rachid Hamid, Nicholas Marcopulos, Roger D Norcross, Lida Qi, Gwendolyn Ramsey, Jenny Tan, Yang Wen, Ramakanth Sarabu
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  ABSTRACT: 7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
  Bioorganic & medicinal chemistry letters 07/2010; 20(14):4140-6. · 2.65 Impact Factor
• Article: Selective GlyT1 inhibitors: discovery of [4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia.

  Emmanuel Pinard, Alexander Alanine, Daniela Alberati, Markus Bender, Edilio Borroni, Patrick Bourdeaux, Virginie Brom, Serge Burner, Holger Fischer, Dominik Hainzl, [......], Robert Narquizian, Mathias Nettekoven, Roger D Norcross, Bernd Puellmann, Philipp Schmid, Sebastien Schmitt, Henri Stalder, Roger Wermuth, Joseph G Wettstein, Daniel Zimmerli
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  ABSTRACT: The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
  Journal of Medicinal Chemistry 06/2010; 53(12):4603-14. · 4.80 Impact Factor
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  Available from: Henri Stalder

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

  Amyaouch Bradaia, Gerhard Trube, Henri Stalder, Roger D Norcross, Laurence Ozmen, Joseph G Wettstein, Audrée Pinard, Danièle Buchy, Martin Gassmann, Marius C Hoener, Bernhard Bettler
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  ABSTRACT: 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.
  Proceedings of the National Academy of Sciences 11/2009; 106(47):20081-6. · 9.68 Impact Factor
• Article: Discovery of benzoylpiperazines as a novel class of potent and selective GlyT1 inhibitors.

  Emmanuel Pinard, Daniela Alberati, Edilio Borroni, Holger Fischer, Dominik Hainzl, Synèse Jolidon, Jean-Luc Moreau, Robert Narquizian, Matthias Nettekoven, Roger D Norcross, Henri Stalder, Andrew W Thomas
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  ABSTRACT: Screening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a structurally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of highly potent compounds displaying excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo efficacy after oral administration.
  Bioorganic & medicinal chemistry letters 08/2008; 18(18):5134-9. · 2.65 Impact Factor
• Article: The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the AB-spiroacetal segment.

  Ian Paterson, Mark J Coster, David Y-K Chen, Renata M Oballa, Debra J Wallace, Roger D Norcross
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  ABSTRACT: The convergent synthesis of the C1-C15 AB-spiroacetal subunit of altohyrtin A/spongistatin 1 is described. This highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc(2)BCl mediation, to establish the C5, C9 and C11 stereocentres, and formation of the desired thermodynamic spiroacetal under acidic conditions. The scalable synthetic sequence developed provided access to multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4.
  Organic & Biomolecular Chemistry 08/2005; 3(13):2399-409. · 3.70 Impact Factor
• Article: Stereocontrolled Total Synthesis of (+)-Altohyrtin A/Spongistatin 1 Financial support was provided by the EPSRC (GR/L41646), Cambridge Commonwealth Trust (Scholarship to M.J.C.), EC (Marie Curie Postdoctoral Fellowship to J.L.A.), DFG (Postdoctoral Fellowship to T.T.), NSERC-Canada (Postdoctoral Fellowship to R.M.O.), Churchill College (Research Fellowship to D.J.W.), Kingapos;s College and Sims Fund, Cambridge (Scholarship to D.Y.K.C.). We also thank Merck and AstraZeneca Pharmaceuticals for ge

  Ian Paterson, David Y.-K. Chen, Mark J. Coster, Jose L. Aceña, Jordi Bach, Karl R. Gibson, Linda E. Keown, Renata M. Oballa, Thomas Trieselmann, Debra J. Wallace, Andrew P. Hodgson, Roger D. Norcross
  Angewandte Chemie International Edition 12/2001; 40(21):4055-4060. · 13.45 Impact Factor
• Article: Stereocontrolled Total Synthesis of (+)‐Altohyrtin A/Spongistatin 1

  Ian Paterson, David Y.‐K. Chen, Mark J. Coster, Jose L. Aceña, Jordi Bach, Karl R. Gibson, Linda E. Keown, Renata M. Oballa, Thomas Trieselmann, Debra J. Wallace, Andrew P. Hodgson, Roger D. Norcross
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  ABSTRACT: An enantioselective total synthesis of spongistatin 1, a.k.a. (+)-altohyrtin A, was achieved via a multistep synthetic sequence which included Wittig olefination, aldol condensation, and macrolactonization. Yes Yes
  Angewandte Chemie International Edition 10/2001; 40(21):4055 - 4060. · 13.45 Impact Factor