Opioid dependence is one of the most serious chronic and relapsing addictive disorders. It has been proven that for many clinical available opiates, both their analgesic function and their notorious side effects (such as addiction and abuse liability) are primarily due to their interaction with the mu opioid receptor (MOR). Our long- term goal is to develop highly selective antagonists for MOR as chemical probes to study MOR structure- efficacy relationship to assist the development of novel potential analgesics with fewer side effects and less addiction and abuse liability. The specific hypothesis behind the proposed research is that 6-heteroaromatic substituted naltrexamine derivatives may act as selective antagonist of MOR. Our hypothesis is based on the following facts: First, a primary series of ligands designed and synthesized as 6-heteroaromatic substituted naltrexamine derivatives have shown high selectivity to MOR. Second, some of these ligands showed strong antagonism to MOR. Third, molecular modeling studies have showed that these ligands may have specific interaction with the extracellular loop (EL) domains of the receptor, especially EL2 and EL3. It has been found out that EL3 of the MOR is very critical for the binding of MOR selective agonists. Site-directed mutagenesis studies have revealed that certain amino acid residues on EL3 may be essential for ligand (including agonist and antagonist) selectivity to MOR. Based on these observations, the focus of this proposal is the synthesis and evaluation of 6-heteroaromatic substituted naltrexamine derivatives as MOR non-peptide antagonists.
The specific aims are: 1. Design and synthesis of novel compounds as mu opioid receptor antagonists based on lead compounds that have been identified from the primary synthesis and pharmacological screening. Homology modeling of MOR and the docking of naltrexone into the MOR model allowed the hypothetical identification of the unique amino acid residues in the binding pocket compared with corresponding (or conserved) loci in the delta and kappa opioid receptor antagonist binding sites. Two series of novel ligands satisfying the requirement of the MOR binding pocket by carrying the unique structural features to interact with EL3 (and/or EL2) of MOR have been designed, synthesized and tested. Two lead compounds have been identified for the preliminary studies. Several new series of ligands have been designed based on the chemical structures of these two lead compounds. The chemical synthesis routes have been proposed in order to materialize these new ligands. 2. Pharmacological evaluation of the compounds synthesized as selective MOR antagonist will be focused on in vitro radioligand-binding assays to determine affinity and selectivity, functional 35S-GTP[3S]-binding assay to determine efficacy, and in vivo behavioral tests. 3. Molecular modeling study- assisted site-directed mutagenesis studies will be conducted to verify the binding mode of the ligands and further characterize the antagonist binding site of the MOR for the next generation antagonist design.

Public Health Relevance

Our long-term goal is to develop highly selective non-peptide antagonists for the mu opioid receptor as chemical probes to study its structure and function relationship in order to assist the development of the potential analgesics without or with less addiction and abuse liability. The focus of this research program is to synthesize and test mu opioid receptor non-peptide antagonists carrying structural features to interact with the extracellular loop region of the receptor, which we anticipate will impart high selectivity for the mu opioid receptor. We believe such ligands will be useful as important pharmacological tools to study the structure-function relationship of the mu opioid receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA024022-05
Application #
8416262
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Hillery, Paul
Project Start
2009-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$310,101
Indirect Cost
$102,675
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Zhang, Yan; Braithwaite, Amanda; Yuan, Yunyun et al. (2014) Behavioral and cellular pharmacology characterization of 17-cyclopropylmethyl-3,14?-dihydroxy-4,5?-epoxy-6?-(isoquinoline-3'-carboxamido)morphinan (NAQ) as a mu opioid receptor selective ligand. Eur J Pharmacol 736:124-30
Arnatt, Christopher Kent; Zhang, Yan (2014) Bivalent ligands targeting chemokine receptor dimerization: molecular design and functional studies. Curr Top Med Chem 14:1606-18
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Zaidi, Saheem A; Arnatt, Christopher K; He, Hengjun et al. (2013) Binding mode characterization of 6*- and 6*-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: application of the 'message-address' concept in development of mu opio Bioorg Med Chem 21:6405-13
Yuan, Yunyun; Elbegdorj, Orgil; Beletskaya, Irina O et al. (2013) Structure activity relationship studies of 17-cyclopropylmethyl-3,14*-dihydroxy-4,5*-epoxy-6*-(isoquinoline-3'-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: preliminary results on the role of electronic characteristics for affin Bioorg Med Chem Lett 23:5045-8
Williams, Dwight A; Smith, Cameron; Zhang, Yan (2013) An efficient procedure for the preparation of natural products bearing the 2-(2-phenylethyl)chromone skeleton. Tetrahedron Lett 54:4292-4295

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