6-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: Dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors

Bromidge, Steven M.; Bertani, Barbara; Borriello, Manuela; Faedo, Stefania; Gordon, Laurie J.; Granci, Enrica; Hill, Matthew; Marshall, Howard R.; Stasi, Luigi; Zucchelli, Valeria; Merlo, Giancarlo; Vesentini, Alessia; Watson, Jeannette M.; Zonzini, Laura

doi:10.1016/j.bmcl.2008.08.084

Cited by 25 publications

(14 citation statements)

References 11 publications

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“…Further screening at other CNS receptors has led to the identification of compounds 3 and 6 as SERT inhibitors as well as 5HT 1A receptor ligands (Chart 1). Based on the pharmacological properties of various CNS receptors, we have hypothesized that an agent which antagonizes the 5HT 1A receptor, inhibits SERT and does not interact avidly with DAT, NET, DA D 2 -like subtypes, 5HT 2C and H 1 receptors will have a potentially superior therapeutic profile as novel antidepressants [11–17]. Thus, the aim of this research was to study the structure-activity relationships of newly designed benzothiazoles in order to understand the contributions of the component parts towards selectivity for the 5HT 1A receptor and inhibition of SERT.…”

Section: Introductionmentioning

confidence: 99%

Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): A search for new dual-acting agents as potential antidepressants

Xiao-lin

Etukala

Eyunni

et al. 2012

European Journal of Medicinal Chemistry

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The synthesis and evaluation of several benzothiazole based compounds are described in an attempt to identify novel dual-acting 5HT1A receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT1A receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT1A receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents. In addition, compound 20 binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT2C receptor, which are desirable properties as selectivity for SERT (and not DAT or NET) is associated with an absence of cardiovascular side-effects.

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Section: Introductionmentioning

confidence: 99%

Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): A search for new dual-acting agents as potential antidepressants

Xiao-lin

Etukala

Eyunni

et al. 2012

European Journal of Medicinal Chemistry

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“…2 (27) 48 with the exception that lysed blood was substituted by 5% horse serum for Streptococcus medium. Double dilutions of tested compounds were prepared in 128-0.5 mg/mL concentration range within microplate wells.…”

Section: General Procedures For the Synthesis Of Compounds 27-31mentioning

confidence: 99%

“…On the other hand, quinoline derivatives are known to possess diverse pharmacological properties such as antioxidant 18,19 , antibiotic 20,21 , cardiovascular 22 , anti-TB 23 , antiplatelet 24 , anticancer 25,26 , receptor antagonists 27 , NK3 receptor antagonists-II 28 , anti-inflammatory 29 , antimicrobial 30,31 , selective estrogen receptor modulators (SERMs) 32 and protein kinase inhibitor 33 . Keeping above in mind, we decided to synthesize conjugates of the above-mentioned moieties to study the biological profile of the resulting product.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of antibacterial and antioxidant activity of novel 2-phenyl-quinoline analogs derivatized at position 4 with aromatically substituted 4H-1,2,4-triazoles

Verbanac

Malik

Chand

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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C NMR, and finally mass spectrometry. All the synthesized compounds were evaluated in vitro for their potential antibacterial activity and their preliminary safety profile was assessed through cytotoxicity assay. Additionally, six selected conjugates were evaluated for their antioxidative properties on the basis of density functional theory calculations, using radical scavenging assay (DPPH) and cellular antioxidant assay. The reported results encourage further investigation of selected compounds and are shading light on their potential pharmacological use.

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“…2) [14][15] as a potential, novel, orally bioavailable, brain penetratable antidepressant with high affinity to SERT and 5-HT 1A/1B/1D receptors. In our design of compound RH-880109, we decided to keep 2-methylpiperazine ring as the best linker identified by the authors [15][16][17] to link the two aromatic entities (benzoxazine and quinoline ring system).…”

Section: Designing the "R" Seriesmentioning

confidence: 99%

“…The Open Conference Proceedings Journal, 2011, Volume 2 49 designed by using dihyroquinolinone ring with substituted fluoro at 7 position documented to increase in 5-HT 1A/1B/1D receptor affinities with the highest affinity towards SERT [16,17] as well as using 2-methylpierazine as a linker (Fig. 4).…”

Section: Selective Serotonin Reuptake Inhibitors (Ssris)mentioning

confidence: 99%

Selective Serotonin Reuptake Inhibitors (SSRIs) with Dual Functionality; Hybrid Anti-Autism Candidates

Ghoneim¹

2011

TOPROCJ

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Autism is a lifelong neurodevelopmental disorder significantly on the rise worldwide. Prevalence rate increased dramatically from 1 case/10000 in the early 90's to 1 case/110 in 2011. The diagnosis is characterized by three main domains: dysfunction in social interaction, communication impairment and repetitive behaviors. Selective Serotonin Reuptake Inhibitors (SSRIs) are currently the drug class of choice for treating autism symptoms. The major drawback of SSRIs is that they take several weeks to become therapeutically efficient. Co-administration of SSRIs with 5-HT 1B/1D receptor antagonists proved to be advantageous over SSRIs alone with respect to the magnitude of brain serotonin levels produced. The theory is that the acute blockade of 5-HT 1B/1D receptor would prevent the negative feedback these autoreceptors exert normally on serotonin release and hence enhance the efficiency of SSRIs (i.e. synergistic effect).We hypothesize to incorporate the dual pharmacophoric profile of serotonin reuptake inhibition and 5-HT 1B/1D antagonism in one single molecule carrying dual functionalities. A library of 12 virtual hybrids was successfully designed. The organic synthesis of two chosen hybrids was completed with full structure elucidation, including elemental analysis and proton-Nuclear Magnetic Resonance.The main outcome of the study is obtaining an unprecedented library of novel hybrid molecules combining serotonin reuptake inhibition with 5HT 1B/1D antagonism in one single molecule. In addition, establishing chemical synthesis and other foundation materials needed for further investigation (In vitro and in vivo pharmacological evaluation) towards our ultimate goal of developing new therapeutic line of autism, where no other lines of treatment have been consistently successful.

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6-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: Dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors

Cited by 25 publications

References 11 publications

Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): A search for new dual-acting agents as potential antidepressants

Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): A search for new dual-acting agents as potential antidepressants

Synthesis and evaluation of antibacterial and antioxidant activity of novel 2-phenyl-quinoline analogs derivatized at position 4 with aromatically substituted 4H-1,2,4-triazoles

Selective Serotonin Reuptake Inhibitors (SSRIs) with Dual Functionality; Hybrid Anti-Autism Candidates

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