Date: 2014-07-07
Type of information: Publication of results in a medical journal
phase: preclinical
Announcement: publication of results in Nature
Company: Heptares Therapeutics (UK)
Product: mGlu5 NAM (negative allosteric modulator) drug candidates
Action mechanism:
Disease:
Therapeutic area: CNS diseases
Country:
Trial details:
Latest
news: * On July 7, 2014, Heptares Therapeutics, a GPCR structure-guided drug discovery and development company, announced the publication of a scientific article describing the first high-resolution X-ray crystal structure of the transmembrane domain of the metabotropic glutamate receptor 5 (mGlu5). The paper was selected for Advanced Online Publication in Nature (Doré, A.S. et al, Structure of the class C GPCR metabotropic glutamate receptor 5 transmembrane domain, 2014, Nature http://dx.doi.org 10.1038/nature13396). In this paper, the authors from Heptares describe the crystal structure of the transmembrane domain of mGlu5 in complex with the negative allosteric modulator (NAM), mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of mGlu5 including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches that regulate receptor signalling.
Heptares has used these new findings to identify several novel differentiated mGlu5 NAM drug candidates with improved potency and pharmacokinetic properties compared to previous molecules. In addition, owing to the close relationship among Class C GPCRs, the enhanced knowledge of the mechanism of action of allosteric modulators for metabotropic glutamate receptors will enable the design of both negative and positive allosteric modulators by providing a template for homology modelling of other Class C GPCRs.
