Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse.
Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics.
School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.
Bronwyn M
BM
Kivell
School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.
Amy W M
AW
Ewald
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA. Electronic address: prisinza@ku.edu.
Thomas E
TE
Prisinzano
D000818:Animals; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism*; D045785:Diterpenes, Clerodane / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D006801:Humans; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027544:Salvia; D016896:Treatment Outcome
D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; C090499:salvinorin A
Addiction; Drug abuse; Kappa-opioid receptor; Salvia divinorum; Salvinorin A