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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Preparation of neoclerodane diterpenes as probes for the opioid receptor system

Lozama, Anthony 01 July 2010 (has links)
While there are a variety of therapeutics that interact with the opioid receptor system, they are not without side effects; including constipation, dysphoria and respiratory depression. A better understanding of the opioid receptor system may yield therapeutic agents with a limited side effect profile. The neoclerodane diterpene, salvinorin A, appears to interact at opioid receptors through a unique mode of action. A better understanding of its interactions with opioid receptors will yield valuable information about the opioid system. In order to probe further how salvinorin A interacts at opioid receptors, a series of novel analogues modified at the C-2 and furan ring were synthesized and evaluated for their ability to interact at opioid receptors. Synthetic methods were identified to modulate the furan ring, including the synthesis of Diels-Alder cycloadducts and phenyl rings derived from a reductive elimination. The cycloadducts are one of the first reported examples of Diels-Alder chemistry being applied to modify a neoclerodane while the phenyl ring analogues are the first to have aromatic rings directly off the salvinorin A core. C-2 sulfonate analogues were found to interact differently then their ester counterparts at opioid receptors while several of the cycloadduct analogues maintained affinity and efficacy demonstrating the furan is not required for opioid receptor activity. These findings demonstrate that salvinorin A is amenable for chemical modification, illustrating its potential as a novel scaffold for the development of opioid ligands.

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