Honors Theses

Date of Award

2019

Document Type

Undergraduate Thesis

Department

Chemistry and Biochemistry

First Advisor

Murrell Godfrey

Relational Format

Dissertation/Thesis

Abstract

In 1960, Dr. Paul Janssen of the Janssen Company synthesized fentanyl. It is a rapid-acting analgesic that, unlike similar analgesics around that time, did not have negative cardiovascular effects. Fentanyl, and its derivatives, are strong μ-opioid receptor agonists. Rates of fatal opioid overdoses involving fentanyl have increases rapidly over the past two decades Due to these increasing concerns related to fentanyl and its derivatives, it is important to not only study fentanyl and its known derivatives, but to also study and understand potential new derivatives and how all these compounds interact with the opioid receptors. This study examined the interactions that take place between fentanyl, and its analogs, and the opioid receptors they interact with in the body. The molecular modeling software, Maestro, was used in order to study these specific interactions. Fentanyl and its analogs were sketched and prepped for docking to the receptors using Maestro. The opioid receptor chosen for this study from came from an available, active-state crystal structure. The data from this study identified specific interactions that take place between these drugs and the binding site of corresponding opioid receptor. The designed derivatives used in this study were derivatives of the following analogs: N-methyl fentanyl, fentanyl, carfentanyl, lofentanyl, remifentanil, sufentanil, and alfentanil. Based on the resulting ligand interaction diagrams, it was determined that many of the fentanyl ligands follow expected binding patterns within the binding pocket. Key residue interactions included aromatic stacking interactions, hydrophobic vi interactions, polar interactions and hydrogen bonding. These interactions corresponded to varying structural changes between fentanyl and its analogs. The interactions and structural changes were used to help better understand the potency and toxicity of fentanyl and fentanyl analogs. Future work will include using the results of this study to help predict potential new analogs of fentanyl before they appear on the drug market. Scientists and law enforcement will have advanced knowledge on various fentanyl related substances to improve both detection and treatment of fatal overdose cases.

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