Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: Discovery of Piclozotan

Kamei, Katsuhide; Maeda, Noriko; Nomura, Kayoko; Shibata, Makoto; Katsuragi-Ogino, Ryoko; Koyama, Makoto; Nakajima, Mika; Inoue, Teruyoshi; Ohno, Tomochika; Tatsuoka, Toshio

doi:10.1016/j.bmc.2005.10.046

Cited by 64 publications

(28 citation statements)

References 22 publications

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“…9). The only reference to the formation of 21 is by Kamei et al, [60] where it was isolated as a minor product in 2.6% yield. Evans and Lockhart [61] proposed that the preference of alkyl migration is due to the electronic effects of the 'ortho' cyclic ether oxygen and presented a resonance structure of 4-chromanone (Fig.…”

Section: Mechanistic Discussion: Schmidt Reactionmentioning

confidence: 99%

The Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams: Some Mechanistic Considerations

2010

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The syntheses of some methoxy-substituted bicyclic lactams, of the types 3 and 4, are reported employing two different conditions for the Schmidt reaction of appropriate ketones and employing two different conditions for the Beckmann rearrangement of the corresponding ketoximes. The alkyl to aryl migration ratios of the reactions were determined by high-performance liquid chromatography analysis of the reactions. The mechanisms of the reactions reported are discussed, some limitations of the reported mechanisms identified, and an alternative mechanism proposed in light of the outcomes of the various reactions. Application of the Schmidt reaction and Beckmann rearrangement was used for the synthesis of some chloro bicyclic lactams, of the types 3 and 4.

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Section: Mechanistic Discussion: Schmidt Reactionmentioning

confidence: 99%

The Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams: Some Mechanistic Considerations

2010

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“…Functional characterization of the most active and selective compounds (1,(13)(14)(15), and BMY-7378) at the 5-HT 1A R was performed according to methods of Stanton and Beer [43] using Cytotoxicity assays were carried out against human neuroblastoma cell line SH-SY5Y. Cells were cultured at 37 °C in a humidified incubator containing 5% CO 2 and feed with DMEM (Lonza) nutrient supplemented with 10% heat inactivated FBS, 2 mM L-glutamine, 100 U/mL penicillin and 100 µg/mL streptomycin.…”

Section: Pharmacologymentioning

confidence: 99%

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

Franchini

Manasieva

Sorbi

et al. 2017

European Journal of Medicinal Chemistry

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Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HTR agonist with a moderate 5-HTR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HTR and α adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HTR partial agonists, the first being outstanding for selectivity (5-HT/α = 80), the latter for potency (pD = 9.58) and efficacy (E = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.

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“…Buspirone [IC 50 for 5-HT 1A =11.0nM, D 2 =55nM, 1 -adrenergic=2920nM] and tandospirone [IC 50 for 5-HT 1A =7.7nM, D 2 =59nM, 1 -adrenergic=2780nM] possess aliphatic and steric volume imide moieties and show affinity for dopamine D 2 receptor. Ipsapirone [IC 50 for 5-HT 1A =5.8nM, D 2 =371nM, 1 -adrenergic= 457nM] possesses a planar aromatic imide moiety and shows an affinity for 1 -adrenergic receptor [24].…”

Section: -Ht 1a Receptor Ligandsmentioning

confidence: 99%

5-Hydroxytryptamine (5-HT) Receptor Ligands

Kitson¹

2007

CPD

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Serotonin (5-HT) receptors are part of the G protein-coupled and ligand-gated ion channel families. 5-HT exerts its diverse actions by binding to cell surface receptors which can be classified into seven distinct families (5-HT1 to 5-HT7) according to their structural diversity and mode of action. Some of the 5-HT families are comprised of multiple receptors which share similar structural and mechanistic properties but display very different operational profiles. Evidence continues to mount in support of the important roles of the 5-HT receptors in various neuropsychiatric disorders such as anxiety, depression, schizophrenia, migraine and drug addiction. The 5-HT receptors may also play an important role in obesity, aggression, sexual behaviour and cardiovascular disorders. A number of selective/non-selective 5-HT agonist and antagonist ligands (drugs) have been developed to challenge many of these disease states.

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Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: Discovery of Piclozotan

Cited by 64 publications

References 22 publications

The Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams: Some Mechanistic Considerations

The Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams: Some Mechanistic Considerations

Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists

5-Hydroxytryptamine (5-HT) Receptor Ligands

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