Carboline- and phenothiazine-derivated heterocycles as potent SIGMA-1 protein ligands

Donnier-Maréchal, Marion; Larchanché, Paul-Emmanuel; Broc, Delphine Le; Furman, Christophe; Carato, Pascal; Melnyk, Patricia

doi:10.1016/j.ejmech.2014.10.053

Cited by 17 publications

(10 citation statements)

References 33 publications

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“…There are conflicting reports on the possible role of neurosteroids in convulsive disorders [176, 177] although the pro-convulsant effects of progesterone appear not to be related to σ1Rs given that σ1R ligands have mostly anti-convulsant effects [178, 179]. As such, recent data on the involvement of σ1R in rare CNS diseases highlights the potential of the ANAVEX 2-73 sigma ligand to treat other CNS disorders, including epilepsy [180]. Additional studies with highly selective σ1R ligands would definitely shed some light on their therapeutic potential as anti-convulsive agents.…”

Section: The Cb1r-nmdar Complexmentioning

confidence: 99%

Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction

et al. 2016

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Glutamate is probably the most important excitatory neurotransmitter in the brain. The glutamate N-methyl-D-aspartate receptor (NMDAR) is a calcium-gated channel that coordinates with G protein-coupled receptors (GPCRs) to establish the efficiency of the synaptic transmission. Cross-regulation between these receptors requires the concerted activity of the histidine triad nucleotide-binding protein 1 (HINT1) and of the sigma receptor type 1 (σ1R). Essential brain functions like learning, memory formation and consolidation, mood and behavioral responses to exogenous stimuli depend on the activity of NMDARs. In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits. The efficacy of such control depends on HINT1/σ1R assisting in the physical coupling between cannabinoid type 1 receptors (CB1Rs) and NMDARs to dampen their activity. Subsequently, the calcium-regulated HINT1/σ1R protein tandem uncouples CB1Rs to prevent NMDAR hypofunction. Thus, early recruitment or a disproportionate cannabinoid induced response can bring about excess dampening of NMDAR activity, impeding its adequate integration with GPCR signaling. Alternatively, this control circuit can apparently be overridden in situations where bursts of NMDAR overactivity provoke convulsive syndromes. In this review we will discuss the possible relevance of the HINT1/σ1R tandem and its use by endocannabinoids to diminish NMDAR activity and their implications in psychosis/schizophrenia, as well as in NMDAR-mediated convulsive episodes.

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Section: The Cb1r-nmdar Complexmentioning

confidence: 99%

Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction

et al. 2016

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“…Our study indicated that the potent anticonvulsant effect of fenfluramine is the result of its complex pharmacological profile, which includes serotonin GPCRs [ 19 , 18 ], σ1Rs, and probably, serotonin metabolism [ 50 , 51 ]. Thus, fenfluramine takes advantage of the utility of σ1R antagonists [ 41 , 40 , 38 ] and of serotonergic substances in the control of seizures and convulsive episodes [ 52 ]. This idea could also apply to monoamine reuptake inhibitors and specific serotonin reuptake inhibitors, such as fluoxetine and citalopram, that exhibit anticonvulsant activity [ 53 ] and display activity at σ1Rs [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although the role of σ1Rs in the pathophysiology of epilepsy has not been fully established, some σ1R ligands such as dextrorphan and carbetapentane ameliorate status epilepticus induced by kainic acid [ 38 , 39 ], and racemic (±)-pentazocine antagonizes electrical tonic convulsions in mice [ 40 ]. Likewise, recent data on the involvement of σ1Rs in rare CNS diseases highlights the potential of the sigma ligand ANAVEX 2-73 to treat epilepsy [ 41 ]. Additional studies with highly selective σ1R ligands would definitely shed some light on their therapeutic potential as anticonvulsive agents.…”

Section: Introductionmentioning

confidence: 99%

Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors

2018

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Fenfluramine exhibits antiepileptic properties and thus diminishes epileptiform discharges in experimental animal models of Dravet syndrome. Fenfluramine is metabolized into norfenfluramine in vivo, which shows greater affinity and agonist activity at serotonin 5HT2 receptors (5HT2R) than fenfluramine. In this study, we found that fenfluramine and norfenfluramine disrupted the regulatory association of the sigma 1 receptor (σ1R) with NR1 subunits of glutamate N-methyl-D-aspartate receptors (NMDAR), an effect that was also produced by σ1R antagonists such as S1RA and prevented by σ1R agonists such as PPCC. The antagonists removed σ1R bound to NMDAR NR1 subunits enabling calcium-regulated calmodulin (CaM) to bind to those subunits. As a result, CaM may inhibit calcium permeation through NMDARs. The serotoninergic activity of fenfluramine at 5HT2AR, and likely also at 5HT2CR, collaborated with its activity at σ1Rs to prevent the convulsive syndrome promoted by NMDAR overactivation. Notably, fenfluramine enhanced the inhibitory coupling of G protein-coupled receptors such as 5HT1AR and cannabinoid type 1 receptor with NMDARs, thus allowing the more effective restrain of NMDAR activity. Thus, fenfluramine circumvents the negative side effects of direct NMDAR antagonists and may improve the quality of life of subjects affected by such proconvulsant dysfunctions.

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“…Despite chemical stability of tic-hydantoin derivatives in neutral and acidic media, they demonstrated a low metabolic stability, preventing from the perspective of drug development. Continuing our efforts in the synthesis of S1R ligands to solve this problem of metabolic stability, other works ( Figure 1) were dedicated to replacement of the tic-hydantoin moieties with different tricyclic heterocycles [40] or benzannulated scaffold [41]. Though the S1R affinity was maintained for most of the compounds (Ki = 0.6 to 30 nM), but the S2R/S1R selectivity remained low (< 30).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands

Donnier-Maréchal

Carato

Larchanché

et al. 2017

European Journal of Medicinal Chemistry

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A series of novel benzamide-derived compounds was designed, synthesized and pharmacologically evaluated. Among all 37 synthesized compounds, two series were developed with the modulation of the nature, the position of atoms or groups on the benzamide scaffold, but also the nature of the amine group separated from the benzamide with 2, 3 or 4 methylene groups. In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2R) revealed that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z. Some selected compounds were also evaluated for their agonist and antagonist activities on a panel of 40 receptors. Results showed the importance of the nature and the position with halogeno atom on the benzamide scaffold, the length chain but also the contribution of the hydrophobic part on the amine group. Among them, compounds 7i, w, y with Cl, CN or NO groups at the 4-position of the benzamide scaffold showed excellent affinity for S1R (Ki = 1.2-3.6 nM), selectivity for S2R (Ki up to 1400 nM) and high selectivity index (IC/Ki ratio from 28 000 to 83 000). Futhermore, these compounds presented an excellent safety profile over 40 other receptors. These derivatives will be selected for further biological investigations.

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Carboline- and phenothiazine-derivated heterocycles as potent SIGMA-1 protein ligands

Cited by 17 publications

References 33 publications

Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction

Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction

Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors

Synthesis and pharmacological evaluation of benzamide derivatives as potent and selective sigma-1 protein ligands

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