Issue 11, 2011
From the journal:

MedChemComm

A highly selective agonist for the metabotropic glutamate receptor mGluR2†

Simon D. Nielsen,‡a   Marica Fulco,‡ab   Michaela Serpi,‡ab   Birgitte Nielsen,a   Maria B. Hansen,a   Kasper L. Hansen,a   Christian Thomsen,d   Robb Brodbeck,d   Hans Bräuner-Osborne,a   Roberto Pellicciari,b   Per-Ola Norrby,c   Jeremy R. Greenwoode  and  Rasmus P. Clausen*a  

* Corresponding authors

a Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark
E-mail: rac@farma.ku.dk
Fax: +45 35 33 60 41
Tel: +45 35 33 65 66

b Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Italy

c Department of Chemistry, Göteborg University, Sweden

d Lundbeck Research USA, Paramus, NJ, USA

e Schrodinger Inc., 120 W 45th St, New York, NY, USA

Abstract

The three conformationally restricted cyclopropyl glutamate analogues (3, 4, 5) were synthesised and their affinity for ionotropic and activity at metabotropic glutamate receptors were probed. Compound 4 turned out to be a highly selective agonist at the metabotropic glutamate receptor mGluR2 with at least two orders of magnitude selectivity in potency compared to the very homologous mGluR3 as well as mGluR1, 4, 5, 7. We also tried to synthesise the two epimers of 6, but the two compounds underwent fast epimerisation in H2O. Furthermore, two cyclopropyl arginine analogues (7, 8) were synthesised and characterised pharmacologically at GPRC6A.

Graphical abstract: A highly selective agonist for the metabotropic glutamate receptor mGluR2

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Article information

DOI
https://doi.org/10.1039/C1MD00186H
Article type
Concise Article
Submitted
20 Jul 2011
Accepted
25 Aug 2011
First published
23 Sep 2011

Med. Chem. Commun., 2011,2, 1120-1124

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A highly selective agonist for the metabotropic glutamate receptor mGluR2

S. D. Nielsen, M. Fulco, M. Serpi, B. Nielsen, M. B. Hansen, K. L. Hansen, C. Thomsen, R. Brodbeck, H. Bräuner-Osborne, R. Pellicciari, P. Norrby, J. R. Greenwood and R. P. Clausen, Med. Chem. Commun., 2011, 2, 1120 DOI: 10.1039/C1MD00186H

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