Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double‐blind, placebo‐controlled trial

Kotajima-Murakami, Hiroko; Takano, Ayumi; Hirakawa, Shinya; Ogai, Yasukazu; Funada, Daisuke; Tanibuchi, Yuko; Ban, Eriko; Kikuchi, Minako; Tachimori, Hisateru; Maruo, Kazushi; Kawashima, Takahiro; Tomo, Yui; Sasaki, Tsuyoshi; Oi, Hideki; Matsumoto, Toshihiko; Ikeda, Kazutaka

doi:10.1002/npr2.12232

Cited by 3 publications

(4 citation statements)

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“…In the second clinical trial, the effects of ifenprodil were examined in patients with methamphetamine use disorder [ 65 , 67 ]. Methamphetamine is one of the most abused drugs in Japan [ 68 ].…”

Section: Pharmacological Modulation Of Girk Channels and Therapeutic ...mentioning

confidence: 99%

“…The primary outcome was the use or nonuse of methamphetamine during the drug administration period in the placebo group vs. the 120 mg/day ifenprodil group (see our previous studies for secondary outcomes). In this clinical trial, we did not find effects of ifenprodil on the primary or secondary outcomes [ 65 , 67 ]. The additional analyses, however, showed that the number of days of methamphetamine use during the follow-up period was lower, and emotional problems on the SRRS improved after treatment with 120 mg/day ifenprodil compared with both the placebo and 60 mg/day ifenprodil groups [ 65 , 67 ].…”

Section: Pharmacological Modulation Of Girk Channels and Therapeutic ...mentioning

confidence: 99%

“…In this clinical trial, we did not find effects of ifenprodil on the primary or secondary outcomes [ 65 , 67 ]. The additional analyses, however, showed that the number of days of methamphetamine use during the follow-up period was lower, and emotional problems on the SRRS improved after treatment with 120 mg/day ifenprodil compared with both the placebo and 60 mg/day ifenprodil groups [ 65 , 67 ]. Importantly, there were no adverse events associated with ifenprodil or placebo administration.…”

Section: Pharmacological Modulation Of Girk Channels and Therapeutic ...mentioning

confidence: 99%

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GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders

2022

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Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1–4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs.

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Section: Pharmacological Modulation Of Girk Channels and Therapeutic ...mentioning

confidence: 99%

Section: Pharmacological Modulation Of Girk Channels and Therapeutic ...mentioning

confidence: 99%

Section: Pharmacological Modulation Of Girk Channels and Therapeutic ...mentioning

confidence: 99%

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GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders

2022

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“…Ifenprodil ( 1 , Figure ) is approved as a cerebral vasodilator in Japan (Cerocral). Additionally, ifenprodil is investigated in serval clinical trials studying its potential for the treatment of diseases like drug addiction and COVID-19. − A positive effect of this negative allosteric modulator could also be shown in animal models of Alzheimer’s disease and neuropathic pain. , Nevertheless, since ifenprodil was developed as an α-antagonist for the treatment of hypertension, it has several side effects related to interactions with σ 1 , σ 2 , α 1 , and 5-HT receptors. − Therefore, the interest in developing highly active and highly selective negative allosteric modulators has increased during the past years. For example, Ro 25-6981 ( 2 ) was developed, which exhibits higher GluN2B affinity and activity than ifenprodil. , …”

Section: Introductionmentioning

confidence: 99%

Indazole as a Phenol Bioisostere: Structure–Affinity Relationships of GluN2B-Selective NMDA Receptor Antagonists

Lüken,

Goerges,

Ritter

et al. 2023

J. Med. Chem.

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Negative allosteric modulation of GluN2B subunit-containing NMDA receptors prevents overstimulation, resulting in neuroprotective effects. Since the phenol of prominent negative allosteric modulators is prone to rapid glucuronidation, its bioisosteric replacement by an indazole was envisaged. The key step in the synthesis was a Sonogashira reaction of non-protected iodoindazoles with propargylpiperidine derivatives. Modification of the alkynyl moiety allowed the introduction of several functional groups. The synthesized indazoles showed very high GluN2B affinity but limited selectivity over σ receptors. Molecular dynamics simulations revealed the same molecular interactions with the ifenprodil binding site as the analogous phenols. In two-electrode voltage-clamp experiments, enantiomeric 3-(4-benzylpiperidin-1-yl)-1-(1H-indazol-5-yl)propan-1-ols (S)-10a and (R)-10a displayed higher inhibitory activity than ifenprodil. In contrast to phenolic GluN2B antagonists, the indazoles were not conjugated with glucuronic acid. It can be concluded that the phenol of potent GluN2B antagonists can be replaced bioisosterically by an indazole, retaining the high GluN2B affinity and activity but inhibiting glucuronidation.

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