Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmacology & Toxicology

First Advisor

Dana Selley


Opioid use disorder (OUD) is a major public health concern in the Unites States, resulting in an estimated 128 overdose deaths per day. Although presently approved OUD pharmacotherapies are partially effective, they are accompanied by undesirable side effects or low compliance. m-Opioid receptor (MOR) agonists (methadone and buprenorphine) are associated with physical dependence, abuse liability and respiratory depression, whereas the MOR antagonist naltrexone is associated with withdrawal precipitation, dysphoria and low patient compliance. Therefore, development of novel medications with fewer side effects and higher compliance than current OUD pharmacotherapies is needed. The objective of this dissertation was to pharmacologically characterize novel 6-substituted naltrexamine analogs in vitro and in vivo to identify ligands that possess improved pharmacological actions.

Receptor and [35S]GTPgS binding assays in opioid receptor-expressing cells were used to determine MOR affinity, selectivity and efficacy of 18 indole analogs of 6a- and 6b-naltrexamine. Results revealed two ligands, NAN and NAM, that exhibited high MOR affinity with moderate and high selectivity over k- and d-opioid receptors, respectively, and the desired low efficacy MOR partial agonism and ability to competitively antagonize full agonists.

NAN and NAM also displayed partial agonism for acute inhibition of adenylyl cyclase activity in MOR-expressing cells. Both of these ligands, along with the previously identified low efficacy MOR ligand NAQ, precipitated less cAMP overshoot than naltrexone in prolonged morphine-treated cells. Conversely, prolonged treatment with these novel ligands induced less naltrexone-precipitated cAMP overshoot than in prolonged morphine-treated cells. Furthermore, mice treated repeatedly with NAQ showed minimal withdrawal signs upon naltrexone challenge, unlike repeated morphine-treated mice. Lastly, NAQ produced dose-dependent conditioned place preference in mice. These findings suggest that MOR-selective low efficacy partial agonists neither produce physical dependence nor precipitate withdrawal but remain rewarding. Such ligands could be further developed to provide OUD pharmacotherapies with improved compliance and safety.


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Available for download on Tuesday, August 05, 2025