Sanford Burnham Prebys Medical Discovery Institute

Yale University

The Salk Institute for Biological Studies

Sanford-Burnham Medical Research Institute

Brown University

Douglas J Sheffler

Nicholas David Peter Cosford

Mitchell Dennis Vamos

Benjamin Turk

Dhanya Raveendra Panickar

Reuben J Shaw

Nicholas Cosford

Matthew Chun

Dhanya Raveendra-Panickar

Daniel F Egan

John Howard Hutchinson

Nicholas D P Cosford

Reto Andreas Gadient

Raveendra Panickar Dhanya

Russell Dahl

Carolina L Haass-Koffler

Stress responses involve corticotropin releasing factor (CRF), the two cognate receptors (CRFand CRF) and the CRF-binding protein (CRFBP). Utilizing a novel cell-based assay, a C-terminal CRFBP fragment [CRFBP(10 kD)] was found to potentiates CRF-intracellular Carelease, demonstrating that CRFBP possesses excitatory roles in addition to the inhibitory role established by the N-terminal fragment of CRFBP [CRFBP(27 kD)]. This interaction was CRF-specific, as CRFresponses were not potentiated by CRFBP(10 kD). As there were currently no small molecule ligands available that selectively interact with either CRFBP or CRF, a cell-based assay was miniaturized, wherein CRFBP(10 kD) was fused as a chimera with CRF, that allowed us to a perform a high-throughput screen (HTS) of approximately 350,000 small molecules. This resulted in the identification of negative allosteric modulators (NAMs) of the CRFBP(10 kD)-CRFcomplex that blunt CRF-induced potentiation of N-Methyl-D-aspartic acid receptor (NMDAR)-mediated synaptic transmission in dopamine neurons in the ventral tegmental area (VTA). These results provide the first evidence of specific roles for CRFand CRFBP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for the treatment of stress and substance abuse disorders such as alcohol use disorder.

Compositions and methods for the modulation of the corticotropin releasing factor binding protein and the treatment of alcohol use disorder

Provided herein are small molecule active metabotropic glutamate subtype-2 and -3 receptor negative allosteric modulators (NAMs), compositions comprising the compounds, and methods of using the compounds and compositions.

Metabotropic glutamate receptor negative allosteric modulators (NAMs) and uses thereof

In certain aspects, the invention provides a method for treating a disease or condition in a subject, the method comprising co-administering to a subject in need thereof a therapeutically effective amount of at least one ULK1-inhibiting pyrimidine, and a therapeutically effective amount of an mTOR inhibitor.

ULK1 inhibitors and methods using same

Provided herein are small molecule active metabotropic glutamate subtype-2 and -3 receptor positive allosteric modulators (PAMS), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

Metabotropic glutamate receptor positive allosteric modulators (PAMS) and uses thereof

Metabotropic glutamate receptor negative allosteric modulators (NAMS) and uses thereof

Growing community of inventors

San Diego, CA, United States of America

Douglas J Sheffler