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Opioid Ligands for the treatment of Alzheimer's Disease (Administrative Supplement on Parent Grant R01DA038635)

Award Number: R01DA038635
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Opioid Ligands for the treatment of Alzheimer's Disease (Administrative Supplement on Parent Grant R01DA038635) - ¿ DESCRIPTION (provided by applicant): Opioids such as morphine are the most potent and efficacious agents currently available for the treatment of moderate to severe acute and chronic pain. These drugs primarily act through the mu subtype of the opioid receptors. However, their therapeutic use is limited due to respiratory depression, opioid-induced bowel dysfunction, development of tolerance and dependence, and renewed concerns around addiction liabilities. There is an urgent unmet medical need for the discovery and development of novel analgesics that are as efficacious as morphine but devoid of significant side effects. Delta receptor gene knockout/knockdown experiments and studies using selective antagonists and bifunctional (mu agonist/delta antagonist) compounds have provided evidence that activation of mu receptor function with simultaneous suppression of delta receptor function produces analgesic effects with greatly diminished mu receptor mediated side effects. Thus, compounds possessing dual but opposing functional activity of mu receptor agonism and delta receptor antagonism have the potential to exhibit broad-spectrum analgesia with a wide safety margin and therapeutic index. Therefore, we have been pursuing the discovery of small molecules possessing the dual functional profile of mu agonism/delta antagonism. To this end, we recently discovered compounds possessing a balanced profile of high-affinity binding at mu and delta receptors and possessing mixed mu agonist/delta antagonist functional activity. In addition these compounds had a diminished propensity to produce tolerance, dependence and abuse liability. In this proposed project, our goal is to develop novel orally active mu agonist/delta antagonist compounds. The approach builds upon the structure-activity relationships determined for the lead series. The medicinal chemistry lead optimization strategy includes rational drug design utilizing crystal structure information on mu and delta receptors that became recently available as well as multi- parametric lead optimization for the improvement of physicochemical and pharmacokinetic properties. To achieve the goal of identifying lead preclinical candidates we will (1) design and synthesize new compounds based upon activity and in vitro pharmacokinetic properties (2) perform in vitro screening to determine opioid receptor binding and functional activity (3) determine the in vitro and in vivo pharmacokinetic profile (bioavailability, half-lifeand CNS levels) to select compounds for (4) comprehensive in vivo analgesic efficacy and side effect profiling in rodents. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, opioid biochemistry and molecular biology, pharmacokinetics, opioid pharmacology, and drug development.


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: 2022 ( Subtotal = $0 )
2022	2019	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	5	7/21/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	5	6/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $1,407,639 )
2019	2019	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	5	6/10/2019	NON-COMPETING CONTINUATION	$880,230
2019	2019	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	001	5	6/11/2019	SUPPLEMENT FOR EXPANSION	$527,409
														Subtotal = $1,407,639

Issue Date FY: 2018 ( Subtotal = $892,417 )
2018	2018	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	4	6/29/2018	NON-COMPETING CONTINUATION	$892,417
														Subtotal = $892,417

Issue Date FY: 2017 ( Subtotal = $882,231 )
2017	2017	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	3	6/6/2017	NON-COMPETING CONTINUATION	$882,231
														Subtotal = $882,231

Issue Date FY: 2016 ( Subtotal = $879,889 )
2016	2016	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVENUE SO, POB 55305	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	2	6/23/2016	NON-COMPETING CONTINUATION	$879,889
														Subtotal = $879,889

Issue Date FY: 2015 ( Subtotal = $912,586 )
2015	2015	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVENUE SO, POB 55305	BIRMINGHAM	AL	35205	JEFFERSON	USA	Drug Use and Addiction Research Programs	000	1	7/20/2015	NEW	$912,586
														Subtotal = $912,586

Grand Total All Awards = $4,974,762

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Opioid Ligands for the treatment of Alzheimer's Disease (Administrative Supplement on Parent Grant R01DA038635)

Award Number: R01DA038635

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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