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Selectively Targeting Opioid Receptor Heterodimers

Award Number: R21DA031574
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2011
PERIOD OF PERFORMANCE END DATE: 01/31/2015

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Selectively Targeting Opioid Receptor Heterodimers - DESCRIPTION (provided by applicant): Selectively Targeting Opioid Receptor Heterodimers 7. Project Summary/Abstract Opioid receptors are important targets for the treatment of acute and chronic pain indications and are one of the few targets currently subject to pharmacological intervention in the treatment of alcoholism. The opioid receptor system is comprised of three highly related receptors: the mu, delta, and kappa opioid receptors (MOR, DOR, and KOR respectively). Studies using knock-out animals have demonstrated that each of these receptors has a unique contribution to nociception and alcohol consumption. Despite more than 50 years of research, several mysteries remain as to the pharmacology of the opioid receptors. In particular, there are pharmacologically-defined subtypes of the MOR, DOR and KOR that exist in vivo that cannot be recapitulated in cell-based systems expressing a single receptor. Thus, it is extremely challenging to design better, more selective opioid drugs until the molecular nature of the pharmacological subtypes has been defined. We propose that heterodimerization of the opioid receptors could alter their pharmacology and explain the opioid subtypes. In particular, several lines of evidence suggest that DOR1 may be a heterodimer complex of MOR and DOR while DOR2 may be a homomer/monomer of DOR. Our preliminary data suggest that agonism of DOR1 reduces drinking and antagonism at DOR2 reduces drinking. Thus, our goal is to design new ligands that are agonists at DOR1 (MOR/DOR heterodimers) but antagonists at DOR2. We have designed a series of novel bivalent ligands that we predict may have these desired properties. We have designed our bivalent ligands to have novel function(s) on heterodimers that are distinct from their effects on homomers/monomers, due to their "tuned affinity". Specifically, each of our bivalent ligands features a high affinity compound tethered to a low affinity compound. We take this approach because one of the inherent drawbacks to "classical" bivalent ligands is that they are not selective for heterodimeric receptors. That is, each pharmacophore in classic bivalent ligands can interact with high affinity with its matching monomeric/homomeric receptor as well as with a receptor that is part of a heterodimer. In the two Specific Aims here, we will generate "tuned affinity" bivalent ligands and use them together with a unique set of tools, including cell lines and a complete set of opioid receptor knock out mice, to probe the functional role of the MOR/DOR heterodimers. PUBLIC HEALTH RELEVANCE: Here, we have designed several new tuned affinity bivalent opioid ligands that we believe will have novel pharmacologies due to their selective activity profile on MOR/DOR heterodimers. We will use these ligands to probe the existence and functional relevance of the MOR/DOR heterodimer.


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: 2014 ( Subtotal = $0 )
2014	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	3	2/21/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = -$7,279 )
2013	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	001	3	9/26/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$106,802
2013	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	2	9/26/2013	NON-COMPETING CONTINUATION	-$114,081
														Subtotal = -$7,279

Issue Date FY: 2012 ( Subtotal = $206,985 )
2012	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	2	1/31/2012	NON-COMPETING CONTINUATION	$206,985
														Subtotal = $206,985

Issue Date FY: 2011 ( Subtotal = $223,910 )
2011	2011	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	1	2/8/2011	NEW	$223,910
														Subtotal = $223,910

Grand Total All Awards = $423,616

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Selectively Targeting Opioid Receptor Heterodimers

Award Number: R21DA031574

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2011

PERIOD OF PERFORMANCE END DATE: 01/31/2015

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