Bioorganic & medicinal chemistry letters
October 18, 2004
Kevin Tidgewell, Wayne W Harding, Mark Schmidt et al.
68 citations
Salvinorin A, a hallucinogen from Salvia divinorum, may serve as a therapeutic for stimulant abuse, but no methods exist to detect it or its metabolites in biological fluids. This work describes a straightforward synthesis of a deuterium-labeled analog of salvinorin A and its use as an internal standard for detecting salvinorin A and its metabolites in biological fluids using LC-MS, providing a tool for studying its metabolism and potential therapeutic development.
Bioorganic & medicinal chemistry letters
June 1, 2013
Warunya Arunotayanun, Jeffrey W Dalley, Xi-Ping Huang et al.
41 citations
Two widely marketed novel psychoactive drugs, alpha-methyl-tryptamine and 5-methoxy-N,N-diallyl-tryptamine, were analyzed for their chemical structure and binding to serotonin receptor subtypes. These tryptamine-derived compounds, sold without restriction, can cause psychosis and hallucinations that may lead to injury or death. The study elucidates their structures and receptor binding profiles, providing insight into their pharmacological actions.
Bioorganic & medicinal chemistry letters
February 1, 2016
Nicholas V. Cozzi, Paul F. Daley
24 citations
N,N-Diallyltryptamine (DALT) and its 5-methoxy derivative (5-MeO-DALT) are tryptamines originally synthesized by Alexander Shulgin, with 5-MeO-DALT reported psychoactive at 12-20 mg and DALT showing few effects at 42-80 mg. This study synthesized additional 5-substituted-DALTs and measured their binding affinities at 45 cloned receptors and transporters. Five DALT compounds had affinities of 10-80 nM for serotonin 5-HT1A and 5-HT2B receptors, while DALT itself had 100 nM affinity at 5-HT1A. Affinities at 5-HT2A receptors were weakest (250-730 nM). Five compounds showed 50-400 nM affinity for 5-HT1D, 5-HT6, and 5-HT7 receptors. Binding also occurred at adrenergic, sigma, histamine, and transporter sites. Quantitative structure-affinity relationships revealed correlations with steric, electronic, and hydrophobic parameters, aiding future drug development.
Bioorganic & medicinal chemistry letters
May 15, 2013
Prabhakar R Polepally, Kate White, Eyal Vardy et al.
24 citations
Salvinorin A, the active ingredient in the hallucinogenic plant Salvia divinorum, is nature's most potent hallucinogen and selectively activates the κ-opioid receptor. To explore how these compounds bind to specific receptors, researchers synthesized a series of dicarboxylic ester derivatives of salvinorin A and tested their binding affinity at κ-, δ-, and μ-opioid receptors. Most of the new compounds showed high affinity for the κ-opioid receptor. The methyl malonyl derivative 4 had the strongest binding, with a Ki of 2 nM, while analogues 5, 7, and 14 also exhibited significant affinity, with Ki values of 21, 36, and 39 nM respectively. These findings provide insights into brain chemistry and ligand-receptor interactions.
Bioorganic & medicinal chemistry letters
September 1, 2018
Shun Hirasawa, Min Cho, Tarsis F Brust et al.
Salvinorin A (SalA) is a potent and selective kappa-opioid receptor agonist, but its chemical instability has hindered medicinal chemistry. Weak bases cause C8 epimerization, which destroys receptor affinity and signaling. Replacing C20 with hydrogen and O6 with CH2 stabilizes the scaffold so completely that epimerization is suppressed. The resulting compound, O6C-20-nor-SalA, retains high potency for kappa-opioid receptor agonism.
Bioorganic & medicinal chemistry letters
October 1, 2010
David Y W Lee, Lu Yang, Wei Xu et al.
Salvinorin A, the main active ingredient of Salvia divinorum, is a potent and selective κ opioid receptor (KOPR) agonist. Researchers synthesized a series of C-2 halogenated analogs of salvinorin A as molecular probes to investigate the binding pocket at the C-2 position, particularly the effects of α versus β configuration. Binding and functional studies showed that β isomers generally bind better than α isomers, except for iodinated analogs. None of the C-2 halogenated analogs improved KOPR binding affinity compared to the parent compound. Functional assays characterized one analog, 6b, as a partial agonist with a maximum effect of 46% of the full agonist U50,488H at 250 nM. Affinity to the kappa receptor increased with atomic radius (I>Br>Cl>F), consistent with halogen bonding interactions.
Bioorganic & medicinal chemistry letters
March 1, 2009
Lu Yang, Wei Xu, Feng Chen et al.
Salvinorin A, the main active ingredient of Salvia divinorum, is a potent and selective kappa-opioid receptor agonist. A series of C-12 triazole analogs and an oxadiazole analog were synthesized and tested for binding affinity at kappa, mu, and delta opioid receptors. Surprisingly, all triazole analogs showed negligible binding affinity at opioid receptors, and the oxadiazole analog, previously reported as a mu and kappa opioid receptor antagonist, exhibited very low affinities and no antagonism in the binding assays. These results suggest that electronic factors affecting either the electron density of a hydrogen bond acceptor at C-12 or hydrophobic interactions between the C-12 moiety and the kappa-opioid receptor are critical for C-12 analog affinity.
Bioorganic & medicinal chemistry letters
November 15, 2007
Kenneth G Holden, Kevin Tidgewell, Alfred Marquam et al.
Removing the C-1 ketone from salvinorin A and its analogue herkinorin changes their activity at opioid receptors. A derivative called 1-deoxo-1,10-dehydrosalvinorin A acts as a moderately potent antagonist at all three opioid receptor subtypes. Herkinorin, a mu opioid agonist, becomes a weak antagonist when its C-1 ketone is removed. These results indicate the C-1 ketone is a key structural feature for mu agonist activity.