Granted Patent
B2
US 12,465,594 · App. 18/486,973 · Granted Nov 11, 2025
Compositions and methods for the modulation of the corticotropin releasing factor binding protein and the treatment of alcohol use disorder
Inventors:
Carolina L. Haass-Koffler (Providence, RI); Douglas James Sheffler (San Diego, CA); Nicholas David Peter Cosford (San Diego, CA)
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Abstract
Stress responses involve corticotropin releasing factor (CRF), the two cognate receptors (CRF 1 and CRF 2 ) 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 Ca 2+ release, 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 2 -specific, as CRF 1 responses were not potentiated by CRFBP(10 kD). As there were currently no small molecule ligands available that selectively interact with either CRFBP or CRF 2 , a cell-based assay was miniaturized, wherein CRFBP(10 kD) was fused as a chimera with CRF 2α , 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)-CRF 2 complex 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 CRF 2 and 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.
Claims (6)
1 . A method of treating a stress response in a subject in need thereof, the method comprising the step of administering to the subject a composition comprising a therapeutically effective amount of a negative allosteric modulator (NAM) of the CRFBP (10 kD)-CRF 2 complex, wherein the NAM is selected from a compound of the formula:
and
wherein the composition downregulates CRF-induced potentiation of N-Methyl-D-aspartic acid receptor (NMDAR)-mentioned synaptic transmission in dopamine neurons and/or increase postsynaptic gamma-aminobutyric acid (GABA) receptor function.
2 . The method of claim 1 , wherein the NAM selectively antagonizes CRF at the CRFBP-CRF 2 complex but lack antagonistic activity toward CRF 2 alone and CRF 1 .
3 . The method of claim 2 , wherein the NAM is a compound of the formula:
4 . The method of claim 2 , wherein the NAM is a compound of the formula:
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 6, 2025
From: SHEFFLER, DOUGLAS JAMES; COSFORD, NICHOLAS DAVID PETER
To: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
Reel/Frame 070127/0456 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 16, 2023
From: HAASS-KOFFLER, CAROLINA L.
To: BROWN UNIVERSITY
Reel/Frame 065223/0786 →
Continuity (4)
Continuation
17273607
Provisional Application
62726830
· Sep 4, 2018
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