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.
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.
|Zheng, Yi; Obeng, Samuel; Wang, Huiqun et al. (2018) Methylation Products of 6?- N-Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators. ACS Chem Neurosci :|
|Wang, Huiqun; Kellogg, Glen E; Xu, Ping et al. (2018) Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling. J Mol Graph Model 83:100-111|
|Obeng, Samuel; Yuan, Yunyun; Jali, Abdulmajeed et al. (2018) In vitro and in vivo functional profile characterization of 17-cyclopropylmethyl-3,14?-dihydroxy-4,5?-epoxy-6?-(isoquinoline-3-carboxamido)morphinan (NAQ) as a low efficacy mu opioid receptor modulator. Eur J Pharmacol 827:32-40|
|Obeng, Samuel; Wang, Huiqun; Jali, Abdulmajeed et al. (2018) Structure-Activity Relationship Studies of 6?- and 6?-Indolylacetamidonaltrexamine Derivatives as Bitopic Mu Opioid Receptor Modulators and Elaboration of the ""Message-Address Concept"" To Comprehend Their Functional Conversion. ACS Chem Neurosci :|
|Cornelissen, Jeremy C; Obeng, Samuel; Rice, Kenner C et al. (2018) Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys. J Pharmacol Exp Ther 365:37-47|
|Pagare, Piyusha P; Wang, Huiqun; Wang, Xiang-Yang et al. (2018) Understanding the role of glucose regulated protein 170 (GRP170) as a nucleotide exchange factor through molecular simulations. J Mol Graph Model 85:160-170|
|Falls, Bethany A; Zhang, Yan (2018) Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach. ACS Chem Neurosci :|
|Pagare, Piyusha P; Zaidi, Saheem A; Zhang, Xiaomei et al. (2017) Understanding molecular interactions between scavenger receptor A and its natural product inhibitors through molecular modeling studies. J Mol Graph Model 77:189-199|
|Wang, Huiqun; Zaidi, Saheem A; Zhang, Yan (2017) Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation. Bioorg Med Chem 25:2463-2471|
|Arnatt, Christopher K; Falls, Bethany A; Yuan, Yunyun et al. (2016) Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization. Bioorg Med Chem 24:5969-5987|
Showing the most recent 10 out of 36 publications