Journal of medicinal chemistry
December 26, 2014
Andrew P Riley, Chad E Groer, David Young et al.
115 citations
Salvinorin A, a compound from the leaves of Salvia divinorum, activates κ-opioid receptors and could be a basis for treating substance abuse. Researchers synthesized several derivatives with modified furan rings to better understand how this part of the molecule binds to the receptor. Functional assays showed that smaller substitutions are preferred, indicating the furan ring fits into a tight part of the binding pocket. The most potent analogue reduced drug-seeking behavior in an animal model of relapse without causing sedation, a common side effect of other κ-opioid agonists.
Journal of medicinal chemistry
September 21, 2006
Thomas H Mclean, Jason C Parrish, Michael R Braden et al.
115 citations
A series of rigid analogues of the hallucinogenic phenethylamine 2C-B was synthesized to determine the active shape these molecules adopt when binding to the 5-HT(2A) receptor. Computer docking predicted that one benzocyclobutene analogue, (R)-2, would be the most potent. Chemical resolution and X-ray crystallography confirmed this: (R)-2 was equipotent to LSD in rats trained to discriminate LSD from saline, making it one of the most potent and selective compounds yet tested in this assay. The compound also acted as a functionally selective agonist at the 5-HT(2A) receptor, showing 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are linked to arachidonic acid production, such selective agonists might lack the intoxicating properties of LSD.
Journal of medicinal chemistry
February 1, 1981
G P Migliaccio, T L Shieh, S R Byrn et al.
34 citations
NMR spectroscopy reveals that the side-chain conformations of bufotenin and psilocin differ in solution. In water, both compounds have similar populations of trans and gauche rotamers. In chloroform, bufotenin shows a slight preference for the trans rotamer, while psilocin strongly favors the gauche form, stabilized by about 1 kcal/mol, possibly due to a weak hydrogen bond. The difference in biological activity between the two compounds is largely explained by their different basicities: the amino group pKa of psilocin is 8.47, compared to 9.67 for bufotenin, which affects their partitioning behavior.
Journal of medicinal chemistry
November 5, 1998
S M Efange, D C Mash, A B Khare et al.
33 citations
Five new compounds derived from a fragment of ibogaine were synthesized and tested for their ability to bind to brain receptors and transporters. All five showed 8 to 10 times stronger binding to the dopamine transporter than ibogaine itself. Two compounds were more potent than ibogaine at the serotonin transporter, while the others were weaker. The compounds generally had weak binding to dopamine D1 and D2 receptors, but two showed moderate binding to dopamine D3 receptors. All had weak binding to opioid receptors and NMDA receptors. These derivatives may serve as useful substitutes for ibogaine in addiction therapy.
Journal of medicinal chemistry
September 22, 2022
Christian B M Poulie, Eline Pottie, Icaro A Simon et al.
32 citations
The serotonin 2A receptor (5-HT2AR) is responsible for the psychedelic effects of certain drugs, which show promise for treating neuropsychiatric conditions. This work examined how a series of compounds, including 25CN-NBOH, signal through two pathways: Gαq and β-arrestin. Disrupting the interaction with a specific amino acid, Ser1593×36, reduced both pathways' potency and efficacy, with Gαq signaling more strongly affected. This led to the creation of the first effective β-arrestin-biased 5-HT2AR agonists (4a-b and 6e-f), which prefer the β-arrestin pathway over Gαq relative to LSD.
Journal of medicinal chemistry
May 9, 2013
Thomas E Prisinzano
22 citations
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, activates opioid receptors—the same targets as morphine—despite being non-nitrogenous, a first for opioid receptor agonists. Its effects also do not involve previously studied psychotomimetic targets. This Perspective describes a research program aimed at developing tools to understand drug tolerance and dependence, with the goal of designing new treatments for pain, drug abuse, and other central nervous system disorders.
Journal of medicinal chemistry
January 12, 2023
Carolyn J Straub, Lisa E Rusali, Kyle M Kremiller et al.
19 citations
Ibogaine, the main psychoactive alkaloid in Tabernanthe iboga, has been studied for decades as a possible treatment for substance use disorders because it may interrupt addiction to multiple drugs. Its inhibition of α3β4 nicotinic acetylcholine receptors in the brain is a likely mechanism for this anti-addictive effect. This perspective examines several classes of compounds developed to target α3β4 nAChRs, focusing on those effective in pre-clinical models of drug abuse and evaluated clinically. It highlights the promising potential of α3β4 nAChRs as viable targets for treating a wide array of substance use disorders and discusses challenges that must be overcome to develop these ligands into therapeutic treatments.
Journal of medicinal chemistry
November 1, 1979
R A Glennon, P K Gessner, D D Godse et al.
17 citations
Bufotenine, a psychoactive compound, has weak behavioral effects in humans and animals, likely because it cannot easily cross the blood-brain barrier. Researchers synthesized several ester derivatives of bufotenine to evaluate them pharmacologically. Unexpectedly, all the esters showed strong affinity for serotonin receptors in isolated rat stomach tissue. Chromatographic analysis indicated that the esters were not extensively broken down into bufotenine during the assay, suggesting the esters themselves may be active at these receptors.
Journal of medicinal chemistry
July 1, 1987
F Babin, T Huynh-Dinh
13 citations
An oxidative coupling method was developed to covalently label serotonin receptors. Oxidizing bufotenine with MnO2 or human ceruloplasmin, then adding dansylcadaverine or dansyllysine, produced a fluorescent adduct with a fused oxazole structure. This approach offers a way to attach fluorescent tags to serotonin derivatives for studying receptor binding.
Journal of medicinal chemistry
March 14, 2024
Lautaro D Alvarez, N R Carina Alves
7 citations
Cannabinoids from Cannabis sativa interact with human proteins called Cys-loop receptors, which mediate inhibitory signals in the nervous system. The binding sites for cannabinoids on these receptors are located within the transmembrane domain, but their exact positions have remained unknown for over a decade. This Perspective describes the computational methods used to identify these binding sites, including analysis of recently resolved cryo-EM structures of zebrafish glycine receptors bound to Δ9-tetrahydrocannabinol and molecular dynamics simulations of the THC-GlyR complex. The work aims to guide future studies on the molecular basis of cannabinoid action on inhibitory channels.
Journal of medicinal chemistry
June 18, 2025
Alexandra Sink, Eline Pottie, Samuel J Carter et al.
2 citations
A photoswitchable ligand for the serotonin 2A receptor (5-HT2AR) was designed to independently study G protein- and β-arrestin2-dependent signaling pathways. The cis-photoisomer binds the receptor with greater affinity than the trans-isomer, at nanomolar concentrations. In functional assays, this ligand showed a preference for recruiting β-arrestin2 over mini-Gαq relative to LSD, offering a tool to investigate β-arrestin2's role in 5-HT2AR signaling and its potential involvement in psychedelic effects.
Journal of medicinal chemistry
January 23, 2025
Allana Cristina Faustino Martins, Bretton Badenoch, Roberto da Silva Gomes
2 citations
Ketamine provides rapid relief for treatment-resistant depression. As an NMDAR antagonist, it may affect prefrontal cortex neurons. The (R)-enantiomer is the most effective and least abuseable antidepressant, though only the (S)-enantiomer is FDA-approved. The metabolite (2R,6R)-Hydroxynorketamine inhibits mGlu2 in presynaptic glutamatergic neurons, increasing BDNF release, which activates TrkB and promotes synaptogenesis. This Perspective explores ketamine's synthesis, pharmacology, metabolism, and effects in animal and human studies to explain differences in biological activity between its enantiomers.
Journal of medicinal chemistry
July 29, 2025
Xu Cheng, Fan Jiang, Lixin Liu et al.
1 citation
A new compound, B11, shows promise as a rapid-acting antidepressant in preclinical models. Unlike existing fast-acting treatments such as esketamine and psychedelics, which carry risks of psychotic side effects and substance abuse, B11 activates the TrkB-CREB signaling axis without interfering with targets linked to those side effects. B11 readily crosses the blood-brain barrier and has a favorable pharmacokinetic profile allowing oral administration. These findings highlight the potential for optimized fast-onset antidepressants to address unmet needs in treating major depressive disorder and underscore the role of neuroplasticity modulation in drug discovery.