Synthesis and pharmacological evaluation of indole-based sigma receptor ligands

Mésangeau, Christophe; Amata, Emanuele; Alsharif, Walid; Seminerio, Michael J.; Robson, Matthew J.; Matsumoto, Rae R.; Poupaert, Jacques H.; McCurdy, Christopher R.

doi:10.1016/j.ejmech.2011.08.031

Cited by 38 publications

(20 citation statements)

References 29 publications

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“…To date, attempts to discriminate σ 2 receptor‐mediated effects in this basic behavioral assay have been hampered by the lack of selective pharmacological tools. Some tetrahydroisoquinolinyl benzamides display high σ 2 receptor affinity and selectivity against σ 1 receptors, as well as low affinity for multiple other receptors (Mach et al, ; Mésangeau et al, ; Tu et al, ). Ligand 1 seemed to be a good candidate for initial behavioral evaluation of this important structural class, as long as critical secondary interactions in vitro and in vivo could be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…Certain tetrahydroisoquinolinyl benzamides, exemplified by 1 (Fig. ), exhibit very high σ 2 receptor affinities and are truly selective in vitro for binding to σ 2 over σ 1 sites (Mach et al, ; Mésangeau et al, ; Tu et al, ). The specific location of the nitrogen within an intact, constrained ring system is key to their exceptional σ 2 receptor affinity and selectivity (Fan et al, ; Xu et al, ).…”

Section: Introductionmentioning

confidence: 99%

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A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Lever

Miller

Green

et al. 2013

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Cocaine functions, in part, through agonist actions at sigma-1 (σ1 ) receptors, while roles played by sigma-2 (σ2 ) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Lever

Miller

Green

et al. 2013

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“…[2,[6][7][8][9][10][11][12][13][14] Methods utilizing C-H activation have also been reported. [15][16][17][18] While transition metal-free Correspondence to: Jimmy Wu.…”

Section: Introductionmentioning

confidence: 99%

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Chen

2017

Angewandte Chemie

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Herein, we report an unprecedented transition metal-free, coupling of indoles with aryl halides. The reaction is promoted by KOtBu and is regioselective for C3 over nitrogen. The use of degassed solvents devoid of oxygen is necessary for the success of the transformation. Preliminary studies implicate a hybrid mechanism that involves both aryne intermediates and non-propagative radical processes. Electron transfer is also a distinct possibility. These conclusions were substantiated by EPR data, isotopic labeling studies, and the use of radical scavengers and electron transfer inhibitors. Graphical AbstractMetals? What metals? Regioselective transition metal-free cross-coupling of aryl halides with indoles at C3 has been reported. The reaction proceeds through an unusual hybrid radical/aryne mechanism. Keywordsindole; transition metal-free; cross-coupling; radical; aryne Indoles with aromatic substituents at C3 are an important class of compounds, many of which possess potent biological activity. For instance, fluvastatin is an FDA-approved HMG-CoA reductase inhibitor that is used in the clinic for lowering LDL cholesterol. [1] Other C3 arylated indoles exhibit pico-to nanomolar inhibitory actions against a wide range of biological targets and processes such as the progesterone receptor, [2] COX-II enzyme, [3] carbonic anhydrase I and II, [4] and tubulin polymerization, [5] etc.The direct introduction of aromatic groups onto an extant indole nucleus at C3 is typically carried out by transition metal-catalyzed cross-coupling reactions (Figure 1). [2,[6][7][8][9][10][11][12][13][14] Methods utilizing C-H activation have also been reported. [15][16][17][18] While transition metal-free Correspondence to: Jimmy Wu. Supporting information for this article is given via a link at the end of the document. processes are rare, they have been accomplished through the use of hypervalent iodine reagents, [19][20][21] diazonium salts, [22] or by means of electrochemistry. [23][24][25] Our group has a longstanding interest in the reaction of indoles and related heterocycles. [26][27][28][29] Herein, we disclose a new approach for the intermolecular C3 arylation of unprotected indoles with simple aryl halides. The reaction is promoted by KOtBu and does not require the use of transition metal catalysts. Preliminary mechanistic investigations point towards an unusual hybrid reaction pathway that exhibits features of both radical and aryne intermediates. Although Daugulis and Tu have reported a limited number of basepromoted C2-and N-selective arylation reactions of indoles, [30][31][32] there appear to be very few precedents for C3-selective variants [32,33] and none that proceed by the proposed hybrid radical/aryne mechanism. HHS Public AccessOptimization studies were carried out on the reaction between indole (1a) and iodobenzene (Table 1). A brief solvent survey identified DMF and DMSO as the only effective solvents (entries 1-5). A reaction performed in the dark resulted in similar yield and selectivity (entry 7 vs 5). ...

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“…Similarly, the other benzylic alcohols 5 and 6 were successfully obtained by subjecting "Grignard reaction" of 4-N,N-dimethylamino benzaldehyde (8) with EtMgBr and PhMgBr, respectively. Next, we investigated the synthesis of N-alkyl indole (7) via N-alkylation, employing commercially available indole (9) with 1,2-dibromoethane (13) in the presence of potassium hydroxide as base and DMF as a solvent (Scheme 3) [64]. In (7).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Antimicrobial Activities of Novel N-Substituted Indole Derivatives

Shaikh

Debebe

2020

Journal of Chemistry

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Indole motifs are one of the most significant scaffolds in the discovery of new drugs. We have described a synthesis of new N-substituted indole derivatives (1-3), and their in vitro antimicrobial activities were investigated. The synthesis of titled compounds has been demonstrated by utilizing commercially available starting materials. The antibacterial and antifungal activities were performed using new strains of bacteria Staphylococcus aureus, Escherichia coli, and Candida albicans using the disc diffusion method. Notably, the compound 4-(1-(2-(1H-indol-1-yl) ethoxy) pentyl)-N,N-dimethyl aniline (1) was found to be most potent than the other analogues (2 and 3), which has shown higher inhibition than the standard drug chloramphenicol.

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Synthesis and pharmacological evaluation of indole-based sigma receptor ligands

Cited by 38 publications

References 29 publications

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Synthesis and Evaluation of Antimicrobial Activities of Novel N-Substituted Indole Derivatives

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