Significance: Salvinorin A, a naturally occurring neoclaridane diterpine and the main active ingredient of the 'magic mint' hallucinogenic plant Salvia divinorum, is a potent and selective k-opioid receptor agonist (Roth et al., Proc Natl Acad Sci USA, 2002). Salvia divinorum and Salvinorin A thus represent a novel class of abused drugs (Sheffler and Roth, Trends Pharmacol Sci, in press) which selectively target the kappa-opioid receptor. The discovery that a diterpine is a selective peptide receptor agonist is unique and unprecedented. Therefore, the elucidation of the structural features responsible for Salvinorin A's actions at k-opioid receptors will illuminate novel approaches for peptide drug design. Investigation of the interaction of Salvinorin A with the k-opioid receptor may also provide a case study representing an innovative strategy for the design of drugs with exceptionally high selectivity. Thus, non-amine ligands, such as salvinorin A, have a potential for nearly absolute selectivity. To accomplish this overall goal we will test the following two hypotheses and 5 specific aims: Hypothesis #1: Salvinorin A interacts with the k-opioid receptor in a unique manner.
Specific aim #1 : To determine the structural features of the k-opioid receptor essential for binding Salvinorin A via a combination of site-directed mutagenesis and molecular modeling.
Specific aim #2 : To determine the structural features of the k-opioid receptor essential for the agonist actions of Salvinorin A at the KOR via a combination of site-directed mutagenesis and molecular modeling approaches.
Specific aim #3 : To compare the mode of binding and activation of the KOR by Salvinorin A with selected alkaloid agonists. Hypothesis #2: The 2-methoxycarbonyl position of Salvinorin A is essential for binding to and activation of the k-opioid receptor.
Specific aim #4 : To compare the binding and functional properties of a series of naturally occurring and synthetic 2-substituted Saivinorin A derivatives. These studies are likely to clarify how Salvinorin A and related drugs of abuse mediate their actions at the molecular and cellular levels and will lead to treatments for the side-effects related to Salvinorin A abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017204-05
Application #
7288375
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (02))
Program Officer
Hillery, Paul
Project Start
2003-09-30
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$280,661
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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