Author ORCID Identifier

Defense Date


Document Type


Degree Name

Master of Science


Pharmaceutical Sciences

First Advisor

Yan Zhang


Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement could lead to development of compounds with different pharmacologic properties. Additionally, exploring other ring systems would diversify and enrich our library of compounds and aid in establishing a comprehensive structure-activity relationship. Therefore, newly synthesized compounds included thiophene derivatives of 6α/β-naltrexamine with potential to be used in the treatment of opioid abuse/addiction. Preliminary in vivo screening revealed that compounds 8 and 11 could be acting as antagonists.

To aid in the design and synthesis of newer generation of MOR selective analogs, a 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Comparative Molecular Field Analysis (CoMFA) on 6β-N-heterocyclic substituted naltrexamine derivatives was conducted. After rigorous optimizations, the best CoMFA model possessed low predictive power. Results obtained suggested that small structural changes could lead to significant change in binding modes of these ligands. To further validate this observation, molecular docking studies were performed which revealed that these ligands indeed possessed multiple distinct binding modes thereby offering rationale for the CoMFA results. Thus, overall this study furnished useful information about the complexity of protein-ligand interactions which will aid in designing more potent and selective MOR ligands.


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