Thienylpyrazoloquinolines with high affinity to benzodiazepine receptors: continuous shift from inverse agonist to agonist properties depending on the size of the alkyl substituent

Shindo, Hitoshi; Takada, Susumu; Murata, Shunji; Eigyo, Masami; Matsushita, Akira

doi:10.1021/jm00126a012

Cited by 41 publications

(29 citation statements)

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“…Infrared spectra acquired on a PerkinElmer 1420 ratio recording spectrometer. A Bruker FT-500 MHz instrument (Brucker Biosciences, U.S.A.) was used to acquire 1 H-NMR spectra; chloroform-d, dimethyle sulfoxide (DMSO)-d 6 and methanol-d 4 were used as solvents. Mass spectra were acquired with a Finnigan TSQ-70 mass spectrometer.…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of New 2-Substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as Anticonvulsant Agents

Zarghi

Hajimahdi

Mohebbi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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The benzodiazepines (BZDs) are widely used in the treatment of central nervous system (CNS) disorders such as anxiety, insomnia and epilepsy.1) The pharmacological effects of the BZDs result from their affinity for a specific binding domain on the gamma amino butyric acid (GABA A ) receptors, known as the BZD receptor. The interaction of BZD agonists with GABA A receptor complex increases the GABA-induced chloride channel opening frequency, which results in membrane hyperpolarization, thus reducing neuronal excitability.2,3) The BZD binding sites in the brain were identified and described by radioligand receptor binding assays and originally it was found that only 1,4-BZD derivatives bind to these receptors. It has since been shown that many groups of compounds bind to the BZD receptor with high affinity, e.g., triazolopyridazines, cyclopyrrolones, quinolines and b-carbolines.4-7) Several pharmacophore models have been proposed for BZDs, and amongst all models suggested for binding to the BZD receptor at least two features are common: an aromatic ring and a coplanar proton accepting group in suitable distance (5 Å). Also, the presence of a second out-ofplane, aromatic ring could potentiate binding to the receptor. [8][9][10][11][12] On this basis, a wide variety of compounds with a chemical structure different from that of BZDs have been synthesized and tested. We recently started a wide research program aimed to design new BZD receptor ligands characterized by a higher degree of flexibility compared with classic BZD ligands. Accordingly, we reported several 1,3,4-oxadiazole derivatives which showed considerable anticonvulsant activity. [13][14][15] As part of our ongoing research program to design new anticonvulsant agents, we describe herein the synthesis and biological evaluation of a novel group of 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles ( Fig. 1) with a flexible second out-of-plane aromatic ring, benzyloxy group which has all the suggested requirements for binding to the BZD receptors. Results and DiscussionChemistry The target 1,3,4-oxadiazole derivatives were synthesized according to Chart 1. Accordingly, reaction of 2-halo-2-benzyloxy benzoic acid methyl ester 1 with hydrazine hydrate in N,NЈ-dimethyleformamide (DMF) at room temperature afforded corresponding 2-halo-2-benzyloxy benzoic acid hydrazide 2 high yields (87-90%).16) The hydrazide were converted to 2-amino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazoles 3 using cyanogen bromide in methanol (71-90%).17) 5-(2-Halo-2-benzyloxyphenyl)-2-mercapto-1,3,4-oxadiazole 4 was prepared by the reaction of hydrazide 2 with carbon disulfide under basic condition (60-70%). 18)Sonication of compound 5 in the presence of suitable alkyl halide in alkaline media afforded 2-alkylthio-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 5a-f (58-90%). 19)Treatment of hydrazide 2 with phenylisothiocyanate followed by reaction with KI/I 2 in alkaline hydro-ethanol gave 2-anilino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 7 (57-80%).20) The compounds we...

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Section: Methodsmentioning

confidence: 99%

Design and Synthesis of New 2-Substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as Anticonvulsant Agents

Zarghi

Hajimahdi

Mohebbi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Over the years, the general scaffold of PQ has been extensively modified, especially on ring A and ring D [152][153][154], which results in compounds with different pharmacological profiles [155,156]. Additionally, studies on the binding site of PQs were performed.…”

Section: Triazoloquinazolinesmentioning

confidence: 99%

Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

et al. 2020

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GABAA receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This review focuses on the synthetic accessibility and potential for library synthesis of GABAA receptor modulators containing at least one heterocyclic scaffold, which were disclosed within the last 10 years.

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“…These ligands allosterically modulate the action of GABA on neuronal chloride ion flux, thus eliciting a wide variety of pharmacological actions ranging in a continuum from Bz-like action (full agonists with anxiolytic, sedative/hypnotic, and anticonvulsant activities) to Bz-opposed action (inverse agonists with proconvulsant and anxiogenic activities), via antagonists which do not exhibit any pharmacological effects per se, but can antagonize the action of both agonists and inverse agonists [1Ϫ4]. Among these compounds, the most interesting classes are β-carbolines I [5], pyrazoloquinolines II [6,7], triazolophthalazines III [8], and pyridodiindoles IV [9] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…These new compounds are structurally related to the pyrazoloquinolines of the CGS series II [6,7], and to the benzothiopyrano [4,3-c]pyridazinones VI [12,13] (Figure 1), which are potent ligands at the BzR. According to Cook's BzR model and in agreement with the binding mode of CGS derivatives [10] (Figure 2), the interaction of pyridothiopyranopyridazinones should be mediated by the imino nitrogen atom at the 1-position, and the carbonyl oxygen atom at the 3-position, which form hydrogen bonds with the two donor sites …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Benzodiazepine Receptor Affinity of Derivatives of the New Tricyclic Heteroaromatic System Pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyridazin‐3(2H,5H)‐one

Primofiore

Settimo

Marini

et al. 2005

Archiv der Pharmazie

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Derivatives 7-13 of a new tricyclic heteroaromatic system, pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one, were prepared as potential ligands at the benzodiazepine receptor, in view of their structural analogy with potent ligands such as the pyrazoloquinolines of the CGS series II, and especially with the benzothiopyrano[4,3-c]pyridazinones VI. They were obtained starting from the versatile ketones 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-one 1 and the corresponding 7-methyl derivative 2, via condensation with glyoxylic acid, and reaction of the intermediate acid mixtures with hydrazine or substituted phenylhydrazines. When evaluated for their binding affinity at the benzo diazepine receptor in bovine cortical membranes, the target compounds 8-13 displayed an affinity in the micromolar/submicromolar order. A hypothesis is presented to rationalize these results.

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Thienylpyrazoloquinolines with high affinity to benzodiazepine receptors: continuous shift from inverse agonist to agonist properties depending on the size of the alkyl substituent

Cited by 41 publications

References 0 publications

Design and Synthesis of New 2-Substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as Anticonvulsant Agents

Design and Synthesis of New 2-Substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as Anticonvulsant Agents

Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

Synthesis and Benzodiazepine Receptor Affinity of Derivatives of the New Tricyclic Heteroaromatic System Pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyridazin‐3(2H,5H)‐one

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