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Featured researches published by Juergen Wichmann.


Bioorganic & Medicinal Chemistry Letters | 1999

Structure-activity relationships of substituted 5H-thiazolo[3,2-a]pyrimidines as group 2 metabotropic glutamate receptor antagonists.

Juergen Wichmann; Geo Adam; Sabine Kolczewski; Vincent Mutel; Thomas Johannes Woltering

A series of 5H-thiazolo[3,2-a]pyrimidine derivatives 1 was studied with respect to the inhibition of 1S,3R-ACPD (10 microM)-stimulated GTP gamma35S binding on rat mGlu2 receptor transfected cell membranes. The influence of substituents at position 6 and 7 as well as the substitution pattern of the two phenyl-rings in position 2 and 5 on the activity is discussed.


Journal of Pharmacology and Experimental Therapeutics | 2015

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lothar Lindemann; Richard Hugh Philip Porter; Sebastian H. Scharf; Basil Kuennecke; Andreas Bruns; Markus von Kienlin; Anthony C. Harrison; Axel Paehler; Christoph Funk; Andreas Gloge; Manfred Schneider; Neil Parrott; Liudmila Polonchuk; Urs Niederhauser; Stephen R. Morairty; Thomas S. Kilduff; Eric Vieira; Sabine Kolczewski; Juergen Wichmann; Thomas Hartung; Michael Honer; Edilio Borroni; Jean-Luc Moreau; Eric Prinssen; Will Spooren; Joseph G. Wettstein; Georg Jaeschke

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non–rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.


Neuroreport | 2002

The orphanin receptor agonist RO 64- 6198 does not induce place conditioning in rats

Gwenaëlle Le Pen; Juergen Wichmann; Jean-Luc Moreau; François Jenck

The abuse liability of Ro 64-6198, an orphanin FQ (OFQ) receptor full agonist that exhibits anxiolytic properties, was evaluated using an unbiased conditioned place preference (CPP) paradigm in rats. As OFQ is structurally related to opioid peptides and also exhibits anxiolytic-like properties, the effect of Ro 64-6198 on CPP was compared with those of morphine and alprazolam. We show here that neither Ro 64-6198 nor alprazolam exhibited rewarding or aversive properties, whereas morphine induced a pronounced CPP. These results strengthen the previous finding that Ro 64-6198 lacked abuse liability in a self-stimulation paradigm, suggesting that this new class of anxiolytic drugs is devoid of the risk for potential non-medical use and dependence.


Bioorganic & Medicinal Chemistry Letters | 2010

Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives : Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists

Thomas Johannes Woltering; Juergen Wichmann; Erwin Goetschi; Frédéric Knoflach; Theresa M. Ballard; Joerg Huwyler; Silvia Gatti

This study completes a series of papers devoted to the characterization of the non-competitive mGluR2/3 antagonist properties of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives with particular emphasis on derivatizations compatible with brain penetration and in vivo activity. Especially the compounds bearing a para-pyridine consistently showed in vivo activity in rat behavioral models after oral administration, for example, blockade of the mGluR2/3 agonist LY354740-induced hypoactivity and improvement of a working memory deficit induced either by LY354740 or scopolamine in the delayed match to position task (DMTP). Moreover, combination studies with a cholinesterase inhibitor show apparent synergistic effects on working memory impairment induced by scopolamine.


Expert Opinion on Therapeutic Patents | 2015

Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005 – present)

Sylvain Celanire; Iyassu K. Sebhat; Juergen Wichmann; Stanislas Mayer; Stephan Schann; Silvia Gatti

Introduction: This review focuses on the medicinal chemistry efforts directed toward the identification of competitive and noncompetitive antagonists of glutamate at group II metabotropic glutamate receptors (mGluRII: mGlu2/3 and mGlu2). This class of compounds holds promise for the treatment of CNS disorders such as major depression, cognitive deficits and sleep-wake disorders, and several pharmaceutical companies are advancing mGluRII antagonists from discovery research into clinical development. Area covered: This review article covers for the first time the patent applications that were published on mGlu2/3 orthosteric and allosteric antagonists between January 2005 and September 2014, with support from the primary literature, posters and oral communications from international congresses. Patent applications published prior to 2005 for which compositions of matter were largely described in peer review articles are briefly discussed with main findings. Expert opinion: Recent advances in the prodrug approach of novel mGlu2/3 orthosteric antagonists combined with the design of novel mGlu2/3 and mGlu2 negative allosteric modulators provide new therapeutic opportunities for neurologic and psychiatric disorders.


Bioorganic & Medicinal Chemistry Letters | 1999

Synthesis of heterocyclic enol ethers and their use as group 2 metabotropic glutamate receptor antagonists

Sabine Kolczewski; Geo Adam; Heinz Stadler; Vincent Mutel; Juergen Wichmann; Thomas Johannes Woltering

Heterocyclic enol ethers of type 1 were studied with respect to the inhibition of 1S,3R-ACPD (10 microM)-stimulated GTP gamma35S binding on rat mGluR2 transfected cell membranes. The structure activity relationship with regard to the substitution pattern of the phenyl ring, the oxygen substituent and the nature of the heterocycle is discussed.


Proceedings of the National Academy of Sciences of the United States of America | 2000

A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat

François Jenck; Juergen Wichmann; Frank M. Dautzenberg; Jean-Luc Moreau; Abdel M. Ouagazzal; James R. Martin; Kenneth Lundstrom; Andrea Cesura; Sonia Maria Poli; Stephan Roever; Sabine Kolczewski; Geo Adam; Gavin J. Kilpatrick


Psychopharmacology | 2002

Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198

Roberto Ciccocioppo; Michela Biondini; Lorena Antonelli; Juergen Wichmann; François Jenck; Maurizio Massi


Neuropharmacology | 2013

Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target

Celia Goeldner; Theresa M. Ballard; Frédéric Knoflach; Juergen Wichmann; Silvia Gatti; Daniel Umbricht


Bioorganic & Medicinal Chemistry Letters | 2005

9H-Xanthene-9-carboxylic acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides as potent, orally available mGlu1 receptor enhancers

Eric Vieira; Joerg Huwyler; Synese Jolidon; Frédéric Knoflach; Vincent Mutel; Juergen Wichmann

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