Journal of Pharmacology and Experimental Therapeutics
November 1, 1995
Piotr Popik, Richard T. Layer, Linda H. Fossom et al.
100 citations
Ibogaine blocks NMDA receptors in a voltage-dependent manner, with a Ki of 2.3 µM at -60 mV in hippocampal cultures, and competitively inhibits [3H]TCP binding to rat forebrain homogenates (Ki, 1.5 µM). It also blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 µM). At doses that interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED50, 64.9 mg/kg) in mice trained to discriminate dizocilpine from saline. Ibogaine reduces naloxone-precipitated jumping in morphine-dependent mice (ED50, 72 mg/kg), an effect abolished by glycine pretreatment. These findings link ibogaine's NMDA antagonist actions to its ability to reduce morphine dependence.
Current Pharmaceutical Design
October 19, 2018
Jeffrey M. Witkin, Daniel E. Knutson, Gabriel J. Rodriguez et al.
44 citations
Conventional antidepressants for major depression, which work by increasing monoamine neurotransmitters, can take weeks to produce a full response, a major limitation. This review describes compounds that provide immediate symptom relief, including ketamine, scopolamine, and newer agents like mGlu2/3 receptor antagonists, negative allosteric modulators of α5-containing GABAA receptors, and psychedelics. These rapid-acting drugs show large effect sizes and efficacy in treatment-resistant patients, though some have challenges with duration of effect and side effects. The proposed mechanism involves amplifying excitatory neurotransmission via AMPA receptors, triggered by increased glutamate efflux. Two compounds, GLYX-13 (Rapastinel) and esketamine, are in late-stage clinical development.
Expert Opinion on Drug Discovery
August 8, 2022
Andrzej Pilc, Agata Machaczka, Paweł Kawalec et al.
20 citations
A new generation of antidepressant drugs is emerging that works faster and helps patients who do not respond to current treatments. Unlike standard antidepressants that take weeks to work, these compounds—including ketamine, psilocybin, and scopolamine—can produce rapid effects, often after a single dose, and their benefits outlast the drug's presence in the brain. Their mechanism involves enhancing AMPA receptor function and antagonizing mGlu2/3 receptors, pointing to a strong glutamatergic component. Based on accumulating preclinical and clinical data, new drug approvals are expected soon.