The Design, Synthesis, and Pharmacological Evaluation of Bifunctional Mu-/Delta-Selective Opioid Receptor Ligands for the Treatment of Pain

Opioid;Peptidomimetic;Medicinal chemistry;Chemistry;Science;Medicinal Chemistry

Nastase, AnthonyTraynor, John R ;

University of Michigan

关键词: Opioid;    Peptidomimetic;    Medicinal chemistry;    Chemistry;    Science;    Medicinal Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/147689/nastase_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Opioid-mediated pain relief, currently the gold standard treatment for many types of pain, has been inextricably associated with negative side effects including analgesic tolerance and physical dependence. These side effects have perpetuated the rising rates of opioid addiction across the United States. Several investigators have shown that activating the mu opioid receptor (MOR) while blocking the delta opioid receptor (DOR) can provide pain relief devoid of tolerance or dependence, laying the foundation for the work presented here. This dissertation is focused on the design and synthesis of bifunctional ligands that both activate MOR and block DOR while binding to both targets with equal affinity. Specifically, this work investigates how substitutions at the N-1, C-6, and C-8 positions of the tetrahydroquinoline (THQ) scaffold impact pharmacological activity. Through these investigations, we have identified two distinct chemical motifs that produce the desired MOR agonist/DOR antagonist efficacy profile. Furthermore, multiple analogues bearing this advantageous efficacy profile also display similar affinity for both targets, improve drug-like properties such as ClogP, and effectively block pain responses in mice after peripheral administration. Additionally, combining those chemical motifs in a hybrid ligand achieved optimal in vitro binding and efficacy, laying a foundation for further exploration. The work discussed herein has yielded 13 novel ligands displaying robust antinociceptive activity; evaluation of tolerance and dependence for select compounds is ongoing.