DOI
https://doi.org/10.25772/RDZJ-ET60
Defense Date
2012
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Malgorzata Dukat
Abstract
There continues to be a need for more effective analgesics. The α2-adrenoceptor (AR) agonist clonidine is an analgesic whose use is severely limited by undesirable side effects. meta-Chlorophenylguanidine (MD-354), an agent developed in our laboratory, selectively potentiates the antinociceptive effects of clonidine in a biphasic manner. Mechanistic studies suggest that both 5-HT3 receptor and α2-AR mechanisms are involved. To further evaluate mechanisms underlying the analgesia-potentiating effect of clonidine by MD-354, pharmacological studies using more established 5-HT3 receptor agonists: meta-chlorophenylbiguanide (mCPBG) and centrally-acting SR57227A, and non-selective α2-adrenoceptor ligand TDIQ, administered alone and in combination with clonidine, were conducted in mouse antinociceptive assays. None of the examined analogs produced an antinociceptive effect when administered alone. Nevertheless, mCPBG potentiated the antinociceptive actions of clonidine in a monophasic manner and the effect was antagonized by the 5-HT3 receptor antagonist tropisetron but not by tropisetron methiodide, suggesting that potentiation is, at least in part, due to a central 5-HT3 receptor mechanism. SR57227A did not alter the antinociceptive actions of clonidine. TDIQ was found to potentiate the analgesic actions of clonidine in a synergistic manner (as determined by an isobolographic analysis) and the effect was blocked by α2-AR antagonists (BRL-44408, imiloxan, ARC-239; α2A-, α2B-, and α2C-AR antagonists, respectively). This supports the hypothesis that MD-354 could be potentiating the analgesic actions of clonidine via an α2-AR agonist mechanism. In order to explore the role of the ring nitrogen atoms and the chloro substituent of conformationally-constrained rotamers of MD-354, analogs of 2-amino-7-chloro-3,4-dihydroquinazoline, with a varying number of nitrogen atoms in the ring were synthesized. Preliminary binding affinity results indicated that the ring nitrogen atoms are essential for 5-HT3 receptor binding. In attempt to explain the varied binding and functional activity of MD-354 at α2-ARs, 3D homology models of α2A-, α2B- and α2C-AR were generated and docking studies of the low-energy rotamers of MD-354 were conducted. The present studies support a role for the involvement of 5-HT3 receptors and α2-ARs in antinociception. Analgesic adjuvants with a dual mechanism of action such as MD-354 might represent a promising avenue to pain treatment.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
August 2012