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Identifying Chemical Modulators of CRF-Binding Protein and CRF Receptor Complexes

Award Number: R33DA029966
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2010
PERIOD OF PERFORMANCE END DATE: 06/30/2016

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Identifying Chemical Modulators of CRF-Binding Protein and CRF Receptor Complexes - DESCRIPTION (provided by applicant): There is accumulating scientific evidence showing that stressors enhance addictive behaviors and are a common cause of relapse to substance abuse. Corticotrophin releasing factor (CRF) is a 41-aa peptide that has been shown to induce various behavioral changes related to adaptation to stress. The CRF system, including the CRF-binding protein (CRF-BP) and the CRF receptors, CRF-R1 and CRF-R2, are thought to contribute, to the physiological adaptations that result from stress. It has also been shown that CRF interaction with CRF-BP may positively modulate CRF-R2 function and, further that when CRF binds to the CRF-BP, it modulates CRF-R2 signaling and contributes to stress-induced relapse to drug seeking. The aim of this application is to identify a chemical series of ligands and compounds that disrupt the interaction between CRF- BP and CRF-R2 to prevent relapse to drug seeking behaviors. Non-peptidyl chemical inhibitors would have advantages over CRF peptides, in terms of cell permeability, stability, and in vivo pharmacology. In the past, this has been difficult due to an inability to develop a suitable high through-put assay for screening against CRF-BP. To address this problem, we have developed an innovative and novel fluorescence based calcium assay where CRF-BP is expressed and tethered at the cell surface in a heterodimeric complex with CRF-R2. This has greatly facilitated our ability to find molecules that inhibit CRF-R2 activation in the presence and absence of CRF-BP. This innovation forms the basis of the high-throughput assay that we have optimized for chemical library screening. We propose to screen a targeted synthetic compound library using this assay and identify chemical inhibitors of CRF-BP-CRF-R2 receptor complex-mediated signaling. Two types of secondary assays will independently confirm any hits. Structure Activity Relations (SAR) and hit to lead optimization will be performed for prototypical inhibitors of the CRF-BP-CRF-R2 receptor complex leading to exploratory pharmacology and preclinical development. Altogether, these efforts will result in validated chemical probes for studying the biology of CRF-BP-CRF-R2 interaction in a variety of cellular and physiological contexts, with the view to developing new therapeutics for treatment of addiction.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2014	ERNEST GALLO CLINIC AND RESEARCH CENTER	5858 HORTON ST STE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	5	11/3/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $487,500 )
2014	2014	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	5	6/25/2014	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2013 ( Subtotal = $468,000 )
2013	2013	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	4	6/14/2013	NON-COMPETING CONTINUATION	$468,000
														Subtotal = $468,000

Issue Date FY: 2012 ( Subtotal = $487,500 )
2012	2012	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	3	7/20/2012	EXTENSION WITH OR WITHOUT FUNDS	$487,500
														Subtotal = $487,500

Grand Total All Awards = $1,443,000

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Identifying Chemical Modulators of CRF-Binding Protein and CRF Receptor Complexes

Award Number: R33DA029966

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2010

PERIOD OF PERFORMANCE END DATE: 06/30/2016

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