ACS Central Science
August 23, 2023
Sarah J Hill, Nathan Dao, Vuong Q. Dang et al.
The salvinorins serve as templates for next generation analgesics, antipruritics, and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we...
Bioorganic & Medicinal Chemistry Letters
September 1, 2018
Shun Hirasawa, Min Cho, Tarsis F. Brust et al.
Salvinorin A (SalA) is a potent and selective agonist of the kappa-opioid receptor (KOR), but its instability has frustrated medicinal chemistry efforts. Treatment of SalA with weak bases like DBU leads to C8 epimerization with loss of receptor affinity and signaling potency. Here we show that replacement of C20 with H and replacement of O6 with CH2 stabilizes the SalA scaffold relative to its...
ACS Central Science
December 27, 2017
Jeremy J Roach, Yusuke Sasano, Cullen L. Schmid et al.
Salvinorin A (SalA) is a plant metabolite that agonizes the human kappa-opioid receptor (κ-OR) with high affinity and high selectivity over mu- and delta-opioid receptors. Its therapeutic potential has stimulated extensive semisynthetic studies and total synthesis campaigns. However, structural modification of SalA has been complicated by its instability, and efficient total synthesis has been...
ChemRxiv
August 19, 2017
Jeremy J Roach, Yusuke Sasano, Cullen L. Schmid et al.
preprint
Salvinorin A (SalA) is a plant metabolite that agonizes the human kappa -opioid receptor (κ-OR) with high affinity and high selectivity over mu- and delta- opioid receptors. Its therapeutic potential has stimulated extensive semi-synthetic studies and total synthesis campaigns. However, structural modification of SalA has been complicated by its instability, and efficient total synthesis has...
Cell
October 20, 2016
Tian Hua, Kiran Vemuri, Mengchen Pu et al.
Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å...
Biological Psychiatry
April 15, 2012
Peter T Nguyen, Cullen L. Schmid, Kirsten M Raehal et al.
Cannabinoid CB(1) receptors (CB(1)Rs) mediate the effects of ▵(9)-tetrahydrocannabinol (THC), the psychoactive component in marijuana. Repeated THC administration produces tolerance and dependence, which limit therapeutic development. Moreover, THC produces motor and psychoactive side effects. β-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these...
Bioorganic & Medicinal Chemistry Letters
January 15, 2012
Cécile Béguin, Justin Potuzak, Wei Xu et al.
The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as pharmacological tools, we have modified 12-epi-salvinorin A, a compound which we have previously observed to be a KOPR partial agonist. Five...
Journal of Neuroscience
October 6, 2010
Cullen L. Schmid, Laura M Bohn
172 citations
Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT 2A R). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT 2A R and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N -methyltryptamines by its...
The FASEB Journal
April 1, 2010
Cullen L. Schmid, Laura M Bohn
Serotonin and the hallucinogenic metabolites of tryptamines, dimethylated tryptamines, activate the serotonin 2A receptor (5‐HT2AR), which is implicated in numerous mental health disorders. We have previously demonstrated that the 5‐HT2AR is differentially regulated by βarrestin2 (βarr2) depending upon the agonist; here we utilized βarr2 knockout mice to compare signaling profiles in vivo, by...
Journal of Medicinal Chemistry
April 24, 2008
Kevin Tidgewell, Chad E Groer, Wayne W Harding et al.
Salvinorin A is a psychoactive natural product that has been found to be a potent and selective kappa opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent kappa opioid receptor signaling yet leads to less receptor downregulation than observed with other kappa agonists. Our initial chemical...
Sarah J Hill, Nathan Dao, Vuong Q. Dang et al.
The salvinorins serve as templates for next generation analgesics, antipruritics and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we...
Etienne Cotter, Giovanni Leoni, Nathan Dao et al.
The salvinorins represent a unique class of polyoxygenated, non-nitrogenous diterpenes that potently and selectively modulate the kappa-opioid receptor (KOR). We recently disclosed a de novo asymmetric synthesis of this scaffold that enabled the discovery of highly potent, biased analogs, including C11-alkynes designed for the CATCH (Clearing-Assisted Tissue Click Chemistry) assay. Here, we...