Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Yan Zhang
Second Advisor
Glen Kellogg
Third Advisor
Dana Selley
Fourth Advisor
Yana Cen
Fifth Advisor
Masahiro Sakagami
Abstract
Structural modification to the mu-opioid receptor (MOR) antagonist, NAY (17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6a-[(2′-pyrrolyl)carboxamido]morphinan) at the 5’-position of the pyrrole ring results in an increase in potency. The parent compound, NAY significantly antagonizes morphine-mediated antinociception, precipitates few withdrawal effects, and possesses favorable oral bioavailability. However, NAY does not potently antagonize morphine-mediated antinociception, which may be due to poor physicochemical properties.It was hypothesized that increasing the lipophilicity of NAY would improve blood-brain barrier permeability and the in vivo potency. As a proof-of-concept, 24 NAY derivatives with different stereochemistry and 12 different substituents at the 5’-position of the pyrrole ring were synthesized. Compound (1) (17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-{[2′-(5′-methylpyrrolyl)]carboxamido}morphinan) hydrochloride) displayed tight binding affinity to the MOR, an improvement in selectivity over the kappa- and delta-opioid receptors relative to NAY, and low efficacy at the MOR. In addition, (1) showed > 3.5-fold increase in potency, antagonizing morphine-mediated antinociception in mice. The improved physicochemical or other ADMET properties may explain the enhancement in potency. A molecular docking study was performed to evaluate the binding pose of NAY and (1) in the MOR. Interestingly, the results indicated that NAY and its derivative made hydrophobic interactions with a putative allosteric site, which suggested that these compounds may behave as bitopic ligands that positively modulate the MOR. Overall, more studies that assess the drug-like properties of (1) need to be conducted to determine how the lead next-generation NAY derivative (1) compares to the parent compound as a candidate to treat opioid use disorder.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-11-2024