Pyridinyl- and pyridazinyl-3,6-diazabicyclo[3.1.1]heptane-anilines: Novel selective ligands with subnanomolar affinity for α4β2 nACh receptors

Deligia, Francesco; Murineddu, Gabriele; Gotti, Cecilia; Ragusa, Giulio; Fasoli, Francesca; Sciaccaluga, Miriam; Plutino, Simona; Fucile, Sergio; Loriga, Giovanni; Asproni, Battistina; Pinna, Gérard Aimè

doi:10.1016/j.ejmech.2018.04.026

Cited by 9 publications

(6 citation statements)

References 18 publications

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“…The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to afford the analytically pure product. The affinities (Ki) of the synthetized compounds for the 42,   and 7 receptors were determined as previously described [1] The Ki (% of coefficient of variation) values shown were calculated by using the LIGAND program to fit the data obtained from at least three independent saturation and competition binding experiments for each compound using the α4β2, α3β4, and α7 subtypes.…”

Section: General Procedures For the Preparation Of Final Compounds 32-47mentioning

confidence: 99%

“…The activation of ionotropic acetylcholine nicotinic receptors (nAChRs) is responsible for several physiological processes; therefore, their modulation could be useful in the treatment of different pathological conditions [1]. Due to their potential therapeutic significance, in particular in the frame of the fight against tobacco addiction, nAChRs have been the subject of extensive researches that led to individuation of bridged piperazines (Figure 1) [2] derived from chemical modification of epibatidine, as unusual pharmacophore for nicotinic ligands [3].…”

Section: Introductionmentioning

confidence: 99%

“…Within these series, the pharmacomodulation on the heteroaromatic ring linked to 3,6-DBH system with different anilines, is responsible for high α4β2 receptor affinity, with Ki ranging from pM to M values, and α7/α4β2 selectivity. Indeed, the substitution with different anilines is well tolerated in term of receptor affinity, mostly for α4β2 subtype and in minor extent for α3β4, whereas seems harmful for α7 receptor subtype, particularly for derivatives of the series typified by 9 [1].…”

Section: Introductionmentioning

confidence: 99%

“…The analytically pure product was isolated by FC as indicated below.Reaction between 15 and 3,4-methylendioxyaniline gave a crude product whose purification by FC (petroleum ether/EtOAc 3:7) afforded 22. White solid; yield 93% (96 mg); mp 78-80 °C 1. H-NMR (200 MHz, CDCl3)  8.41 (s, 1H), 8.18-8.28 (m, 1H), 8.11 (bs, 1H, NH exch.…”

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confidence: 99%

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Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors

Murineddu

Gotti

Asproni

et al. 2019

European Journal of Medicinal Chemistry

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We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with 42 Ki value of 10 pM and a very high7/42 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for 42 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.

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Section: General Procedures For the Preparation Of Final Compounds 32-47mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors

Murineddu

Gotti

Asproni

et al. 2019

European Journal of Medicinal Chemistry

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“…Recently, it was found that Mcl-1 induces conformational irregularity in Bax and inhibits cytochrome c translocation [18]. Various compounds have been found to be useful for the treatment of cancers through activation of various pathways [19][20][21]. The present study investigated the ability of methanol extract of Viburnum grandiflorum to inhibit lung cancer cell growth.…”

Section: Introductionmentioning

confidence: 96%

Induction of Apoptosis in Lung Cancer Cells by Viburnum grandiflorum via Mitochondrial Pathway

Han

Huang

2020

Med Sci Monit

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Departmental sources Background:Lung cancer is one of the leading causes of mortality and morbidity. Viburnum grandiflorum is a medicinal herb known for its wide spectrum of pharmacological activities, but its anti-cancer properties against lung cancer cells have not been previously investigated. The present study elucidated the antitumor effect and associated mechanism of methanol extract of Viburnum grandiflorum extract (VGE) against lung cancer cells. Material/Methods:The viability of H1650, HCC827, and H1299 cells was measured using MTT assay. Apoptosis and cell cycle progression were determined by flow cytometry using annexin-V/PI and JC-1 stains, respectively. The Lipofectamine Plus reagent (Invitrogen) was used for transfection of caspase-9 plasmid to H1650 and H1299 cells. Results:The results showed decreased H1650, HCC827, and H1299 cell viability by VGE, which occurred in a concentration-and time-dependent manner. The VGE treatment significantly increased the rate of apoptosis in H1650 (P<0.05) and H1299 (P<0.02) cells at 48 and 72 h. Treatment of H1650 and H1299 cells with 10 µM of VGE significantly enhanced the number of cells in sub-G1 phase. The VGE treatment cleaved pro-caspase-8/-9 and-3 in H1650 and HCC827 cells at 72 h. The VGE treatment of H1650 and HCC827 cells reduced Mcl-1 protein expression. Treatment of H1650 and HCC827 cells with VGE markedly decreased the level of p-Akt. However, dominant-negative caspase-9 (caspase-9 dN) plasmid transfection prevented the viability-inhibitory effect of VGE on H1650 and HCC827 cells. Treatment of H1650 and HCC827 cells with VGE increased levels of cytochrome c in the cytosol. Conclusions:VGE inhibited lung carcinoma cell viability by apoptosis activation through a caspase-dependent pathway. Therefore, VGE is a potent anti-cancer agent against lung cancer cells.

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Pyridazines and Their Benzo Derivatives

Chinigo

Feng

Hoy

et al. 2022

Comprehensive Heterocyclic Chemistry IV

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Pyridinyl- and pyridazinyl-3,6-diazabicyclo[3.1.1]heptane-anilines: Novel selective ligands with subnanomolar affinity for α4β2 nACh receptors

Cited by 9 publications

References 18 publications

Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors

Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors

Induction of Apoptosis in Lung Cancer Cells by Viburnum grandiflorum via Mitochondrial Pathway

Pyridazines and Their Benzo Derivatives

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