Semester

Spring

Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Rae R. Matsumoto

Committee Co-Chair

Andrew Coop

Committee Member

Stephen G. Graber

Committee Member

Jason D. Huber

Committee Member

Charles D. Ponte

Abstract

The three opioid receptor subtypes, mu (mu), delta (delta) and kappa (kappa) have long been associated with analgesia. Traditional opioid analgesics exert their effects through mu receptors located in the CNS. Recent studies suggest that the development of opioid analgesics displaying dual properties of mu agonism and delta antagonism could be of benefit by retaining potent analgesic properties while reducing the development of tolerance with chronic administration. UMB 425 displays high affinity at the mu receptor (K i = 3.2 +/- 0.14 nM), moderate affinity at the delta and kappa receptor. In vitro [35S]GTPgammaS functional assay results indicate that UMB 425 acts as partial agonist at the mu receptor, whilst having competitive antagonistic properties at the delta receptor. UMB 425 displays potent acute analgesic activity in vivo for both the hot plate and tail-flick assays, comparable to morphine itself. Naloxone, a non-selective opioid antagonist, and nor-BNI, a selective kappa-antagonist, pretreatment studies were performed to ensure proper opioid-induced analgesic mechanisms. Naloxone attenuates the analgesic effects induced by an acute ED90 of UMB 425, while nor-BNI shows no significant reduction. A chronic dosing paradigm was designed to determine UMB 425 induced analgesic tolerance. UMB 425 maintains significantly higher levels of analgesia compared to morphine on the fifth day of this chronic dosing paradigm. A dose-response challenge performed on the sixth day of this paradigm indicates a smaller shift in respective ED50 values for UMB 425 as compared to morphine for both the tail-flick (1.3-/6.4-fold) and hot plate (3.0-/7.8-fold) assays, effectively demonstrating reduced analgesic tolerance liabilities for UMB 425.

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