We are proposing to develop new kappa opioid receptor (KOR) targeted drugs for the treatment of drug addiction. Our primary goal is to identify antagonists and partial agonists as these may be the most promising candidates for treating addiction to and preventing relapse. KOR antagonists represent a target that may be clinically efficacious for improving recovery outcomes following treatment for multiple types of drugs of abuse, including cocaine, methamphetamine, opiates, alcohol, cannabis and nicotine. While KOR antagonists do exists, they have unusually long acting pharmacological profiles (several weeks after single injection) which may ultimately obscure their therapeutic potential. Currently, there are no approved therapies for poly- drug abuse, therefore, given the promise of such antagonists, this proposal has been directed to the NIH program announcement: """"""""Medications Development for Polydrug Addictions Treatment"""""""" (PAS: 08-186). Over the past 3 years, we have been working with the NIH-sponsored Molecular Libraries Probe Centers Network (MLPCN) to identify novel probes and scaffolds at the KOR (1X01MH084153-01). After screening the MLPCN compound collection at the Sanford-Burnham Center for Chemical Genomics (300,000 structurally diverse small molecule compounds), 4 novel chemical entities were discovered that display promising selectivity, potency and efficacy at this receptor. In addition, independent chemistry efforts identified a fifth chemical scaffold that is also unique, and highly selective of the kappa opioid receptor. This proposal seeks 5 years of support to provide the initial preclinical characterizations and chemical optimizations of these compounds into drug candidates. In line with this goal, we will fully characterize the pharmacological properties of the compounds across functionally diverse cell-based assays with of a goal of identifying compounds capable of fine-tuning KOR responsiveness. Cell-based responses will be validated in mouse models assessing antinociceptive activity (for basic determination if the compound has antagonist properties in vivo) as well as for its ability to disrupt stress-induced reinstatement of cocaine conditioned place preference. Drug metabolism and pharmacokinetics of the compounds will be performed to provide information for continued medicinal chemistry optimization rounds. Our enthusiastic team consists of established medicinal and synthetic chemists and an opioid neuropharmacologist (with both molecular and behavioral pharmacology expertise). We are supported by a GPCR pharmacologist with extensive experience in industry-level assay development for high throughput drug discovery as well as an expert in pharmacokinetic evaluations.

Public Health Relevance

Chronic drug abuse and addiction leads to neurological changes in dopaminergic structures in the brain. The kappa opioid receptor is located on neurons that modulate dopamine tone and may present a means to fine tune abrogate dopamine signaling in the addicted brain. Since no viable therapies are currently available for treating wide-ranging addictions, this proposal has been designed to provide the preclinical optimization required to make new kappa opioid receptor- targeted drugs available for the treatment of addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA031927-01
Application #
8162056
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (56))
Program Officer
Kline, Richard
Project Start
2011-06-01
Project End
2016-04-30
Budget Start
2011-06-01
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$724,631
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
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Ho, Jo-Hao; Stahl, Edward L; Schmid, Cullen L et al. (2018) G protein signaling-biased agonism at the ?-opioid receptor is maintained in striatal neurons. Sci Signal 11:
Roach, Jeremy J; Sasano, Yusuke; Schmid, Cullen L et al. (2017) Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent ?-OR Agonist. ACS Cent Sci 3:1329-1336
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Brust, Tarsis F; Morgenweck, Jenny; Kim, Susy A et al. (2016) Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal 9:ra117
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Bohn, Laura M; Zhou, Lei; Ho, Jo-Hao (2015) Approaches to Assess Functional Selectivity in GPCRs: Evaluating G Protein Signaling in an Endogenous Environment. Methods Mol Biol 1335:177-89
Frankowski, Kevin J; Slauson, Stephen R; Lovell, Kimberly M et al. (2015) Potency enhancement of the ?-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif. Bioorg Med Chem 23:3948-56
Luttrell, Louis M; Maudsley, Stuart; Bohn, Laura M (2015) Fulfilling the Promise of ""Biased"" G Protein-Coupled Receptor Agonism. Mol Pharmacol 88:579-88
Zhou, Lei; Stahl, Edward L; Lovell, Kimberly M et al. (2015) Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTP?S binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting. Neuropharmacology 99:131-41

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