Synapse
January 1, 2000
Richard B Rothman, Michael H. Baumann, Christina M Dersch et al.
933 citations
Stimulants like amphetamine, MDMA, and methamphetamine are known to produce reinforcing effects in animals through the brain chemical dopamine. However, their subjective effects in humans—such as euphoria or alertness—may rely more on norepinephrine. Using lab tests, the authors measured how several stimulants affect the release of norepinephrine and dopamine. They found that all tested drugs were most potent at releasing norepinephrine. Crucially, the oral doses that produce amphetamine-like subjective effects in people correlated with the drugs' ability to release norepinephrine, not dopamine, and did not lower prolactin levels (a marker of dopamine release). These findings suggest norepinephrine may play a key role in the subjective experience of stimulants in humans.
Proceedings of the National Academy of Sciences of the United States of America
September 3, 2002
Bryan L. Roth, Karen Baner, Richard B Westkaemper et al.
782 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, potently and selectively activates kappa opioid receptors while having no effect on the serotonin 5-HT(2A) receptor targeted by classical hallucinogens like LSD. This makes it the first known naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A produces perceptual distortions, the findings suggest that kappa opioid receptors play a key role in modulating human perception and that kappa opioid-selective antagonists could be developed as novel treatments for disorders involving perceptual distortions, such as schizophrenia, dementia, and bipolar disorders.
Psychopharmacology
March 15, 2006
Michael H. Baumann, Xiaoying Wang, Richard B Rothman
269 citations
High doses of MDMA (ecstasy) reduce serotonin levels in the brains of rats, but this reduction does not necessarily indicate that neurons have been damaged. The drug works by stimulating the release of serotonin, norepinephrine, and dopamine. At doses that cause long-term serotonin depletion (10-20 mg/kg), markers of actual neuronal damage such as cell death or gliosis are not reliably increased. Even moderate doses that do not deplete serotonin can produce lasting anxiety-like behaviors in rats, suggesting potential risks from the drug beyond neurotoxicity.
Pharmacological Reviews
June 1, 2011
Christopher W Cunningham, Richard B Rothman, Thomas E Prisinzano
109 citations
Salvinorin A, the psychoactive compound in the Salvia divinorum plant, activates kappa-opioid receptors (KOP) to produce its intense hallucinogenic effects, making it the first known non-nitrogenous opioid receptor agonist. Unlike classic hallucinogens such as LSD and mescaline, its effects do not involve the 5-HT(2A) receptor. Research into its structure has yielded receptor probes and tools to study its psychological effects. Salvinorin A shows therapeutic potential for treating pain, mood disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloid compounds can serve as scaffolds for developing drugs targeting aminergic G-protein coupled receptors.
The Journal of pharmacology and experimental therapeutics
August 1, 2006
Michael Ansonoff, Jiwen Zhang, Traci Czyzyk et al.
101 citations
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, produces pain relief (antinociception) and lowers body temperature in mice by activating the kappa-opioid receptor. These effects were observed after injection of salvinorin A or a similar compound, salvinorinyl-2-propionate, into the brain of normal mice, but not in mice genetically lacking the kappa-opioid receptor. Salvinorin A showed high affinity specifically for the kappa-1 subclass of opioid receptors. In contrast, salvinorin B, an inactive derivative, had no effect on pain or body temperature. The findings confirm that salvinorin A acts through the kappa-opioid receptor to produce its behavioral effects.
Synapse
July 14, 2004
Xiaoying Wang, Michael H. Baumann, Heng Xu et al.
101 citations
Two weeks after giving rats MDMA (7.5 mg/kg, three doses) or the toxin 5,7-DHT, the study measured serotonin levels and two protein markers in brain regions. MDMA reduced tissue serotonin by about 50% in cortex, hippocampus, and caudate but did not significantly change the amount of serotonin transporter or glial fibrillary acidic protein, a marker of nerve damage. In contrast, 5,7-DHT reduced serotonin by over 90%, lowered serotonin transporter protein by 20–35%, and increased glial fibrillary acidic protein by 30–39%. The authors conclude that this MDMA regimen does not cause degeneration of serotonin nerve terminals and that lasting serotonin depletion can occur without destroying the axons.
Psychopharmacology
October 1, 2014
Bruce E. Blough, Antonio Landavazo, Ann M Decker et al.
99 citations
Synthetic hallucinogenic tryptamines, including those originally described by Alexander Shulgin, are abused in the USA. While all psychoactive tryptamines act as agonists at serotonin 2A (5-HT₂A) receptors, their varied subjective effects suggest additional neurochemical mechanisms. This work evaluated 21 tryptamines for interactions with serotonin receptor subtypes and neurotransmitter transporters. Eight compounds released serotonin, thirteen inhibited serotonin uptake or were inactive. All were 5-HT₂A agonists with varying potencies; few activated 5-HT₁A receptors. Most recruited β-arrestin via 5-HT₂A. Serotonin transporter (SERT) activity may contribute significantly to some compounds' pharmacology. Releasers tended to be structurally smaller compounds. Two tertiary amines acted as selective SERT substrates, challenging the view that releasing activity requires primary or secondary amines.
Synapse
October 1, 1995
Jean Lud Cadet, Bruce Ladenheim, Hiroshi Hirata et al.
81 citations
Mice carrying extra copies of the human superoxide dismutase gene are protected against MDMA-induced damage to brain dopamine neurons. Normal mice showed large drops in striatal dopamine and its metabolite DOPAC one day and two weeks after a single MDMA injection. Mice with one copy of the transgene showed dopamine loss only at one day, while mice with two copies showed no loss at either time point. Three repeated injections caused dopamine loss in normal mice, small losses in one-copy mice, and no loss in two-copy mice. Serotonin levels were unaffected in all groups. The findings indicate that superoxide radicals contribute to MDMA's dopamine toxicity.
The Journal of pharmacology and experimental therapeutics
February 1, 2007
Richard B Rothman, Daniel L Murphy, Heng Xu et al.
75 citations
Salvinorin A, a hallucinogenic compound that activates kappa-opioid receptors, also partially inhibits mu-opioid receptor binding through an allosteric mechanism. In cells expressing human mu-opioid receptors, salvinorin A reduced binding of two different radioligands (DAMGO and diprenorphine) in a dose-dependent, nonlinear way, altering both the number of binding sites and their affinity. It also slowed the dissociation of these ligands from the receptor and acted as an uncompetitive inhibitor of receptor signaling. Similar effects were observed in rat brain tissue. Together, these findings indicate that salvinorin A modulates the mu-opioid receptor allosterically, not by binding at the same site as typical opioids.
Annals of the New York Academy of Sciences
October 1, 2004
Michael H. Baumann, Robert D. Clark, Allison G. Budzynski et al.
71 citations
The combination of the piperazine analogs BZP and TFMPP mimics the neurochemical effects of MDMA in rat brain. MDMA stimulates transporter-mediated release of serotonin (5-HT) and dopamine (DA), with greater effect on serotonin. BZP selectively releases DA, while TFMPP selectively releases serotonin. Coadministration of BZP and TFMPP produces elevations in extracellular serotonin and dopamine that mirror MDMA's effects, and at high doses, the rise in dopamine exceeds the sum of each drug alone, suggesting drug-drug synergism. These findings provide a basis for recreational use of the combination to mimic MDMA.
Journal of Pharmacology and Experimental Therapeutics
May 1, 2001
Michael H. Baumann, Richard B Rothman, John Pablo et al.
69 citations
Ibogaine, a compound with potential anti-addiction properties, is rapidly converted in the body to noribogaine. In rats, intravenous ibogaine caused dose-related tremors, while noribogaine did not. Both compounds raised stress hormones (corticosterone and prolactin), but ibogaine was more potent for corticosterone. Neither altered dopamine levels in the nucleus accumbens, but both increased extracellular serotonin, with noribogaine being about 10 times more potent as an indirect serotonin agonist. In vitro tests showed both inhibit serotonin uptake. Noribogaine appears biologically active and less likely to cause adverse effects, suggesting it may be a safer alternative for medication development.
Journal of Natural Products
January 1, 2006
Wayne W Harding, Matthew Schmidt, Kevin Tidgewell et al.
59 citations
Salvinorin A, a hallucinogen from the plant Salvia divinorum, is unique as the first non-nitrogenous compound known to bind to opioid receptors. To understand why it selectively targets kappa opioid receptors, researchers systematically altered its structure and tested the effects on receptor binding and activity. This work describes chemical transformations of salvinorin A, including a semisynthesis of salvinicins A and B. It also identifies compound 10a as the first neoclerodane diterpene with delta opioid antagonist activity, providing new tools for studying opioid receptor interactions.
MedChemComm
December 1, 2011
Katherine M Prevatt-Smith, Kimberly M Lovell, Denise S Simpson et al.
50 citations
A modified compound, initially derived from a potent natural hallucinogen, surprisingly offers a new avenue for treating drug addiction. Scientists hypothesized that slight structural changes could enhance its therapeutic benefits. Through synthesizing and evaluating new versions, particularly focusing on their interaction with opioid receptors and impact on drug-seeking behaviors in rats, a specific analog was identified. This novel compound not only matched the original's potency at key brain receptors but also effectively reduced cocaine-induced drug-seeking. This discovery represents the first instance of such a modified compound demonstrating anti-addictive capabilities.
Journal of Natural Products
April 25, 2011
Anthony Lozama, Christopher W Cunningham, Michael J Caspers et al.
40 citations
New chemical methods using microwave heating enabled the first successful Diels-Alder cycloaddition reactions on the furan ring of salvinorin A, a neoclerodane diterpene natural product. This approach introduced electron-withdrawing groups and bulky aromatic rings at the C-12 position. Some of the resulting cycloadducts, specifically dimethyl- and diethylcarboxylate analogues, retained affinity and selectivity for kappa opioid receptors and acted as full agonists. However, converting these cycloadducts into planar phenyl ring systems reduced their receptor affinity. The work provides a novel strategy for rapidly exploring structure-activity relationships of furan-containing natural products.
PLoS One
January 1, 2013
Tamara Antonio, Steven R Childers, Richard B Rothman et al.
36 citations
Iboga alkaloids, including ibogaine, its metabolite noribogaine, and the synthetic compound 18-methoxycoronaridine (18-MC), were tested for their ability to activate the μ-opioid receptor (MOR), a common target of opioid drugs. In rat thalamic membranes, all three compounds acted as antagonists, blocking the receptor rather than activating it, with functional Ke values ranging from 3 μM for ibogaine to 13 μM for noribogaine and 18-MC. None of the compounds stimulated MOR-related G protein activity in cells expressing human or rat MORs, and only limited partial agonist effects were seen in mouse MOR-expressing cells. The findings indicate that an opioid agonist mechanism does not explain these alkaloids' effects on opioid withdrawal, supporting a novel mechanism of action and justifying further search for alternative targets.
Bioorganic & medicinal chemistry
May 1, 2012
Kimberly M Lovell, Tamara Vasiljevik, Juan J Araya et al.
35 citations
A palladium-catalyzed cross-coupling reaction (Liebeskind-Srogl) applied to a modified natural product scaffold produces ketone analogs of salvinorin A at neutral pH and room temperature, expanding synthetic access to this class. A one-step microwave method converts salvinorin A to its 12-epimer, previously requiring multiple steps. Several new analogs (alkene 9 and aromatic compounds 12, 19, 23, 25, 26) retain affinity and selectivity for kappa opioid receptors (KOP), and the furan-2-yl analog (31) shows similar affinity to the parent compound. These results indicate that diverse aromatic groups attached to the decalin core may be tolerated by KOP receptors, potentially yielding additional ligands.
Drug Metabolism and Disposition
October 19, 2013
Marta Concheiro, Michael H. Baumann, Karl B. Scheidweiler et al.
32 citations
MDMA, an illicit drug with potential clinical use for PTSD and anxiety, shows nonlinear accumulation in male rats due to metabolic autoinhibition. After doses of 2.5, 5, and 10 mg/kg, MDMA and its metabolite MDA increased more than proportionally with dose, while other metabolites remained constant. Serotonin syndrome severity correlated with MDMA concentrations, and core temperature correlated with MDA concentrations, suggesting distinct mechanisms for behavioral and hyperthermic effects. At 2.5 mg/kg, MDMA Cmax was 164 ± 47.1 ng/ml, with HHMA and HMMA as major metabolites and less than 20% converted to MDA. These findings, given similarities to human pharmacokinetics, support using rat data at clinically relevant doses.
Tetrahedron
December 20, 2008
Gianfranco Fontana, Giuseppe Savona, Benjamín Rodríguez et al.
32 citations
Salvinorin A, a compound from the hallucinogenic mint Salvia divinorum, is the only known non-nitrogenous and specific kappa-opioid agonist. Several related compounds from Salvia splendens and a series of semisynthetic derivatives, including some with a pyrazoline structural moiety, were tested for their ability to bind to human mu, delta, and kappa opioid receptors. None of these compounds showed high-affinity binding to these receptors. However, one compound (10) showed modest affinity for kappa receptors, suggesting that other naturally occurring neoclerodanes from different Salvia species may have opioid affinity.
Tetrahedron
February 21, 2009
Gianfranco Fontana, Giuseppe Savona, Benjamín Rodríguez et al.
12 citations
Salvinorin A is a unique naturally occurring compound that activates κ-opioid receptors without containing nitrogen. Researchers modified the A ring of salvinorin A and related compounds from Salvia splendens and a non-natural derivative, producing new molecules. When tested for opioid receptor activity, none of these derivatives were active. The absence of activity may be due to the presence of a lactone group at specific positions in the molecular structure.
Annals of the New York Academy of Sciences
May 1, 1998
Michael H. Baumann, Richard B Rothman, Syed F. Ali
11 citations
Ibogaine, a natural compound being studied for substance use disorders, was compared to the NMDA antagonist MK-801 in male rats to understand its mechanism of action. Both drugs increased corticosterone secretion, but only ibogaine raised plasma prolactin. Ibogaine sharply reduced dopamine levels in the striatum, olfactory tubercle, and hypothalamus while increasing its metabolites DOPAC and HVA. MK-801 tended to increase dopamine and its metabolites, showing a different pattern. Neither drug affected serotonin systems. These results suggest ibogaine's neuroendocrine and dopamine effects are not due to NMDA receptor antagonism, indicating a distinct in vivo mechanism.
Organic & biomolecular chemistry
September 21, 2009
Denise S Simpson, Kimberly M Lovell, Anthony Lozama et al.
Modifying the furan ring of salvinorin A, the active component of Salvia divinorum, produced new compounds with activity at opioid receptors. A computational study predicted salvinorin A to be a reproductive toxicant in mammals, suggesting its use may have adverse effects. Two new compounds, piperidine 21 and thiomorpholine 23, were identified as selective partial agonists at kappa opioid receptors. This suggests further structural changes could yield ligands with good opioid receptor selectivity but lower toxicity.
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.