Invited Speaker

Orthosteric Agonists of Group III Metabotropic Glutamate Receptors (mGluR). From Virtual Screening to Potential Therapeutic Effects
Francine C. Acher, C. Selvam, N. Triballeau, N. Oueslati, I. Lemasson, C. Beurrier, S. Lopez, C. Goudet, M. Amalric, H.-O. Bertrand, and J.-P. Pin
France

Metabotropic glutamate receptors (mGluRs) are promising therapeutic targets for several CNS disorders because of their modulatory role in glutamatergic synaptic transmission. In particular activation of presynaptic group III receptors showed beneficial effects in animal models of Parkinson’s disease. Large efforts were made to discover allosteric modulators of these receptors, however orthosteric agonists may also be of therapeutic value if they hold the required ADMET properties. We thus initiated a program aiming at the discovery of such agonists. In a virtual high throughput screening of the mGlu4 receptor binding site, we identified a hit that was optimized in a series of derivatives. While it had been difficult in the past to find new orthosteric ligands of group III mGlu receptors, a large number of these new compounds were able to activate these receptors. Among them LSP1-2111 revealed a marked preference for subtype 4 versus 8, the two most similar group III subtypes. LSP1-2111 was then further evaluated at native receptors and in an animal model of Parkinson disease. Most interestingly, it produced antiparkinsonian effects at 10 fold lower doses than with previously known agonists (e.g. L-AP4, ACPT-I and (1S,2R)-APCPr) and was systemically active (Beurrier et al. FASEB J. 2009).