The Journal of biological chemistry
October 5, 2007
Miriam T Jacobs, Yuan-Wei Zhang, Scott D Campbell et al.
149 citations
Ibogaine, a hallucinogenic alkaloid reported to help treat addiction, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, reducing the maximum transport rate (Vmax) with little effect on serotonin's binding affinity (Km). It also competitively blocks binding of a cocaine analog to SERT, increasing the apparent dissociation constant (KD) without altering the number of binding sites (Bmax). Ibogaine increases reactivity of cysteine residues in the proposed cytoplasmic permeation pathway of SERT but slows reactivity of cysteines in the extracellular pathway. These findings suggest ibogaine binds to and stabilizes the SERT state from which serotonin dissociates into the cytoplasm, opposite to cocaine's action, which stabilizes the state that binds extracellular serotonin.
The Journal of biological chemistry
June 21, 1996
N Almaula, B J Ebersole, D Zhang et al.
147 citations
The neurotransmitter serotonin (5-HT) activates the 5-HT2A receptor by binding through its amine group to a specific aspartate residue. Computer simulations suggested that serotonin also forms a hydrogen bond with a nearby serine residue, but other ligands like LSD and N,N-dimethyl serotonin cannot form this bond due to steric hindrance. Mutating the serine to alanine reduced serotonin affinity 18-fold, and to cysteine reduced it 5-fold, while LSD affinity was unaffected. N,N-dimethyl serotonin showed a small 3-fold decrease only with alanine mutation. These results identify a binding mode where two receptor side chains interact with the same functional group of certain ligands, orienting them in the binding pocket and potentially affecting receptor activation.
The Journal of biological chemistry
May 25, 2012
Simon Bulling, Klaus Schicker, Yuan-Wei Zhang et al.
124 citations
Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, unlike all other known inhibitors which compete with serotonin. It binds to a distinct site accessible from the cell exterior, not the substrate-binding site, and increases accessibility in the cytoplasmic permeation pathway. Ibogaine also noncompetitively inhibits the dopamine transporter (DAT) and blocks substrate-induced currents in both transporters. The inhibition is not reversed by increasing substrate concentration, and ibogaine does not form a long-lived complex with SERT but binds directly to the inward-open conformation. A kinetic model distinguishes ibogaine's noncompetitive action from cocaine's competitive action.
The Journal of biological chemistry
October 14, 2016
Pieter Beerepoot, Vincent M Lam, Ali Salahpour
59 citations
Mutations in the dopamine transporter (DAT) gene cause hereditary dopamine transporter deficiency syndrome (DTDS), a rare condition often involving defective transporter trafficking and folding. Screening known DAT ligands revealed that bupropion and ibogaine increase DAT surface expression, while cocaine and methylphenidate do not. These drugs raise wild-type DAT protein levels and promote maturation of the ER-retained mutant K590A, an effect blocked by inhibiting ER-to-Golgi transport or by knocking down the COPII component SEC24D. Both drugs also rescue maturation and functional activity of DTDS-associated mutations A314V and R445C. This is the first demonstration of pharmacological chaperoning of DAT, suggesting a potential therapeutic approach for DTDS and related conditions.
The Journal of biological chemistry
February 2, 2007
Timothy A Vortherms, Philip D Mosier, Richard B Westkaemper et al.
40 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, binds selectively and potently to the kappa-opioid receptor (KOR). Unlike most ligands for peptide-binding receptors, it is non-nitrogenous and lipid-like. Using chimeric receptors, mutagenesis, accessibility methods, and modeling, the study found that helix 2 of KOR is essential for binding, with two valine residues (Val-108 and Val-118) conferring selectivity. Modeling suggested these residues indirectly affect binding by rotating helix 2. Accessibility experiments comparing KOR and the delta-opioid receptor, which does not bind salvinorin A, showed differential water accessibility of key residues, indicating that differences in helix 2 orientation are critical for salvinorin A's selective binding to KOR.
The Journal of biological chemistry
October 1, 2023
Xue Chen, Jing Li, Lisa Yu et al.
13 citations
A novel indolethylamine N-methyltransferase (RmNMT) from the cane toad (Rhinella marina) was identified and characterized. This enzyme catalyzes the biosynthesis of psychedelic alkaloids such as DMT, 5-methoxy-DMT, and bufotenin, which accumulate in toad skin and parotid glands and have been used ceremonially by Mesoamerican peoples. RmNMT is an effective catalyst not subject to product inhibition and exhibits substrate promiscuity, enabling production of various substituted indolethylamines for purification, pharmacological screening, and metabolic stability assays. Binding evaluations at serotonin receptors showed that primary amines have enhanced affinity at the 5-HT1A receptor compared with tertiary amines. Except for 6-substituted derivatives, N,N-dimethylation protected against catabolism by liver microsomes.
The Journal of biological chemistry
September 1, 2023
Omar B Sanchez-Reyes, Gregory Zilberg, John D McCorvy et al.
10 citations
Opioids, cannabinoids, and psychedelics all act by binding to G protein-coupled receptors (GPCRs), which mediate their inebriating, lethal, and therapeutic effects. Recent structural studies reveal the molecular mechanisms of drugs like fentanyl, tetrahydrocannabinol, and lysergic acid diethylamide at their respective GPCR subtypes. These insights facilitate drug discovery, both for developing treatments to combat substance abuse and for harnessing the therapeutic potential of certain drugs.