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Design and synthesis of small organic molecules as blockers of neuronal calcium ion channels relevant to neuropathic pain
thesis
posted on 2018-07-27, 00:34 authored by Anjali SairamanOver the last decade, there has been extensive research into the identification of drug leads to treat chronic pain, which are presented in Chapter 1. Of relevance to this work are the peptides ω-Conotoxins, isolated from the marine cone snail that belongs to the genus Conus. ω-Conotoxin GVIA binds essentially irreversibly and selectively to the Cav2.2 channel, a validated target for the treatment of neuropathic pain and is thus considered as a potential lead for drug development. ω-Conotoxin GVIA has a number of key amino acid residues that are crucial for its biological activity. Small molecule peptidomimetics of ω-Conotoxin GVIA that possess a benzothiazole core scaffold structure and appropriate side-chain mimics have been previously reported by our group.
In the hope of improving the Cav2.2 channel inhibition, a comprehensive structureactivity relationship study of the previously reported benzothiazole mimetic was undertaken.
Twenty seven compounds were synthesized and all were tested for Cav2.2 and Cav3.2 channel inhibition using FLIPR assay. Our synthetic approach to these compounds, their
biological activity and pharmacokinetic properties are discussed in Chapter 2. Chapter 3 discusses the effect of conformational restriction on binding to neuronal calcium ion
channels, which was studied using three different scaffolds with in-built structural rigidity. Eleven compounds were synthesized, and a couple of them exhibited good Cav2.2 inhibition. Chapter 4 details the development of lower molecular weight analogues which involved substituted phenoxyanilides and pyrimidine based compounds. Commendable Cav2.2 and Cav3.2 inhibition activity were observed in both the scaffold series. Finally, Chapter 5 contains the overall summary and conclusions drawn from this thesis. Our efforts to address the need to treat neuropathic pain accomplished a series of compounds with different scaffolds with moderate Cav2.2 and Cav3.2 channel inhibition.
Twenty seven compounds were synthesized and all were tested for Cav2.2 and Cav3.2 channel inhibition using FLIPR assay. Our synthetic approach to these compounds, their
biological activity and pharmacokinetic properties are discussed in Chapter 2. Chapter 3 discusses the effect of conformational restriction on binding to neuronal calcium ion
channels, which was studied using three different scaffolds with in-built structural rigidity. Eleven compounds were synthesized, and a couple of them exhibited good Cav2.2 inhibition. Chapter 4 details the development of lower molecular weight analogues which involved substituted phenoxyanilides and pyrimidine based compounds. Commendable Cav2.2 and Cav3.2 inhibition activity were observed in both the scaffold series. Finally, Chapter 5 contains the overall summary and conclusions drawn from this thesis. Our efforts to address the need to treat neuropathic pain accomplished a series of compounds with different scaffolds with moderate Cav2.2 and Cav3.2 channel inhibition.
