Synthesis and structure–activity relationship of new 1,5-dialkyl-1,5-benzodiazepines as cholecystokinin-2 receptor antagonists

Roberts, Karen; Ursini, A.; Barnaby, Robert J.; Cassarà, Paolo; Corsi, Mauro; Curotto, Giovanni; Donati, Daniele; Feriani, Aldo; Finizia, Gabriella; Marchioro, Carla; Niccolai, Daniela; Oliosi, Beatrice; Polinelli, S.; Ratti, Emiliangelo; Reggiani, Angelo; Tedesco, Giovanna; Tranquillini, Maria Elvira; Trist, D.G.; Amsterdam, Franciscus T.M. van

doi:10.1016/j.bmc.2011.05.057

Cited by 15 publications

(5 citation statements)

References 31 publications

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“…Alhough the transformation was sluggish, a large excess of AlI 3 furnished the deprotection in moderate yield (Scheme 2E). 32 The method was applied in syntheses of four coumarin analogues (39~42) applicable to organic light emitting displays as fluorescent dyes. Key intermediate 3-hydroxytriphenylamine (38) was prepared in a two-step procedure: Ulmann coupling of iodobenzene and m-anisidine (36) furnished anisole 37; demethylation of 37 with AlI 3 afforded 38 in 93% yield (Scheme 2F).…”

Section: Solvent Effectsmentioning

confidence: 99%

Application of aluminum triiodide in organic synthesis

Tian¹,

Sang²

2015

Arkivoc

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The multifaceted reactivity of aluminum triiodide (AlI 3 ) is reviewed. The oxophilic character of the Lewis acid enables the formation of coordination complexes with esters, ethers, oxiranes, diols, Noxides, and sulfoxides that decompose spontaneously to afford acids, alcohols and olefins via ester and ether cleavage, deoxygenation of oxiranes, and deoxydehydration of diols, respectively. As an iodide ion source and hydrogen iodide precursor, the reagent allows iodination and reduction of Noxides, sulfoxides and azides as well as hydroiodination of alkenes and alkynes. Aluminum enolates, generated by treatment of -haloketones with AlI 3 , provide accesses to -hydroxy ketones, 1,5-diones, and β-iodo Morita-Baylis-Hillman esters.

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Section: Solvent Effectsmentioning

confidence: 99%

Application of aluminum triiodide in organic synthesis

Tian¹,

Sang²

2015

Arkivoc

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“…(a) benzodiazepine group: L-365,260, L-36 718 (devazepide), CI-988, YM022, Z-360, YF476 (netazepide), and YM022 [30][31][32][33]; (b) tryptophan dipeptide derivatives: PD-134,308 [28,34]; (c) ureidoacetamides: RP-73,870 [35]; (d) pyrazolidinones -LY-288,513 [36]. Despite the progress in developing several CCK 2 receptor agonists/antagonists [12,[37][38][39][40][41][42][43][44][45][46], none of them have reached the clinic, because of unfavorable, insufficient, and various biological effects discovered in clinical trials [39]. Only netazepide and Z-360 are currently under clinical development for the management of gastric neuroendocrine tumors and pancreatic cancer, respectively.…”

Section: Introductionmentioning

confidence: 99%

Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists

Paudel¹,

Park²,

Seong³

et al. 2023

J. Integr. Neurosci.

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Background: Cholecystokinin (CCK) is one of the most abundant peptides in the central nervous system and is believed to function as a neurotransmitter as well as a gut hormone with an inverse correlation of its level to anxiety and depression. Therefore, CCK receptors (CCKRs) could be a relevant target for novel antidepressant therapy. Methods: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein.Results: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1-3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022. Conclusions: The results of this study suggest bromophenols 1-3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression.

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“…The prototypic compound of the 2,3-BDZ family, 7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466; Figure ) was first introduced in the 1980s and has been used as a template and standard in the synthesis and activity evaluations of new GYKI compounds . While the 2,3-BDZs’ structures (Figure ) have different pharmacological activity besides their effect on the central nervous system, they also possess anti-inflammatory, antimicrobial, vasopressin antagonist, endothelia antagonist, cholecystokinin antagonist, antithrombotic, anti-HIV, and antiproliferative activities . Hence, there is a keen interest in 2,3-BDZ for applications in numerous fields besides neurology.…”

Section: Introductionmentioning

confidence: 99%

Ortho versus Meta Chlorophenyl-2,3-Benzodiazepine Analogues: Synthesis, Molecular Modeling, and Biological Activity as AMPAR Antagonists

et al. 2020

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2,3-Benzodiazepine compounds are an important family of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists that act in a noncompetitive manner. Due to the critical role of AMPARs in the synapse and various neurological diseases, significant scientific interest in elucidating the molecular basis of the function of the receptors has spiked. The analogues were synthesized to assess the functional consequence of removing the amine group of the phenyl ring, the potency and efficacy of inhibition by substituting a halogen group at the meta vs ortho position of the phenyl ring, and layout the prediction of potential drug candidates for AMPAR hyperactivation. Using the whole-cell patch-clamp technique, we assessed the effect of the derivative on the amplitude of various AMPA-type glutamate receptors and calculated the desensitization and deactivation rates before and after treatment of HEK293 cells. We noticed that the amino group is not necessary for inhibition as long as an electron-withdrawing group is placed on the meta position of the phenyl ring of BDZ. Furthermore, compound 4a significantly inhibited and affected the desensitization rate of the tested AMPARs but showed no effect on the deactivation rate. The current study paves the way to a better understanding of AMPARs and provides possible drug candidates of 2,3-BDZ different from the conventional derivatives.

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Synthesis and structure–activity relationship of new 1,5-dialkyl-1,5-benzodiazepines as cholecystokinin-2 receptor antagonists

Cited by 15 publications

References 31 publications

Application of aluminum triiodide in organic synthesis

Application of aluminum triiodide in organic synthesis

Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists

Ortho versus Meta Chlorophenyl-2,3-Benzodiazepine Analogues: Synthesis, Molecular Modeling, and Biological Activity as AMPAR Antagonists

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