Ulens C.,Catholic University of Leuven |
Spurny R.,Catholic University of Leuven |
Thompson A.J.,University of Cambridge |
Alqazzaz M.,University of Cambridge |
And 7 more authors.
Structure | Year: 2014
Pentameric ligand-gated ion channels (pLGIC) catalyze the selective transfer of ions across the cell membrane in response to a specific neurotransmitter. A variety of chemically diverse molecules, including the Alzheimers drug memantine, block ion conduction at vertebrate pLGICs by plugging the channel pore. We show that memantine has similar potency in ELIC, a prokaryotic pLGIC, when it contains an F16S pore mutation. X-ray crystal structures, using both memantine and its derivative, Br-memantine, reveal that the ligand is localized at the extracellular entryway of the channel pore, and the pore is in a more closed conformation than wild-type ELIC in both the presence and absence of memantine. However, using voltage clamp fluorometry we observe fluorescence changes in opposite directions during channel activation and pore block, revealing an additional conformational transition not apparent from the crystal structures. These results have important implications for drugs such as memantine, which block channel pores. © 2014 Elsevier Ltd. All rights reserved. Source
Cid J.M.,Janssen Cilag SAS |
Tresadern G.,Janssen Cilag SAS |
Duvey G.,Molecular science |
Duvey G.,Addex Therapeutics |
And 21 more authors.
Journal of Medicinal Chemistry | Year: 2014
We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders. © 2014 American Chemical Society. Source