Year of Publication

2011

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department

Chemistry

First Advisor

Dr. Peter A. Crooks

Second Advisor

Dr. Robert B. Grossman

Abstract

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissus damage or described in terms of such damage. Opioids are effective in treating moderate to severe pain, but opioid alone therapy is associated with several adverse effects, development of tolerance and addiction potential. One way to solve these problems is to administer opioids with adjuvant drugs. In this project several opioid molecules were combined with other adjuvant drugs in a single chemical entity to form a codrug.

A series of codrugs were prepared by conjugation of an opioid with S-(-)-nornicotine, ketamine, norketamine and gabapentin. Several of the synthesized codrugs were evaluated for analgesic activity in the rats after oral administration. Codeine-S-(-)- nornicotine, 3-O-acetylmorphine-S-(-)-nornicotine, and N-ethoxycarbonylgabapentincodeine codrugs showed greater effectiveness as well as prolonged pain management properties as compared to the parent drugs. Stabilities of several synthesized codrugs were studied in aqueous solutions from pH 1.3-7.4, in simulated gastrointestinal fluids, in rat plasma and in brain homogenate. Only the ester-linked codrugs showed sign of hydrolysis in different solutions. Carbamate-linked codrugs didn’t cleave under any hydrolytic condition. Pharmacokinetic study was performed on the following three codrugs: 3-O-acetylmorphine-S-(-)-nornicotine, N-acetylgabapentin-codeine, and N-ethoxycarbonylgabapentin- codeine. The carbamate linkage in 3-O-acetylmorphine-S-(-)- nornicotine codrug did not cleave in vivo to produce parent drugs. The ester linkage in N-acetylgabapentin- codeine codrug cleaved in vivo to produce codeine and N-acetylgabapentin, but N-acetylgabapentin did not undergo hydrolysis to produce gabapentin. The ester linkage in N-ethoxycarbonylgabapentin-codeine codrug hydrolyzed slowly in plasma to produce N-ethoxycarbonylgabapentin and codeine and then the carbamate linkage in N-ethoxycarbonylgabapentin hydrolyzed even slowly to produce gabapentin. Produced codeine also metabolized to generate some amount of morphine. Thus, the design and synthesis of an opiate and gabapentin codrug was achieved which was stable enough in the gastrointestinal tract, showed enhanced analgesic effects as compared to the physical mixture of the parent drugs, and also produced the two parent drugs in blood plasma.

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