- Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1AReceptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
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Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints"that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
- Sniecikowska, Joanna,Gluch-Lutwin, Monika,Bucki, Adam,Wi?ckowska, Anna,Siwek, Agata,Jastrzebska-Wiesek, Magdalena,Partyka, Anna,Wilczyńska, Daria,Pytka, Karolina,Latacz, Gniewomir,Przejczowska-Pomierny, Katarzyna,Wyska, El?bieta,Weso?owska, Anna,Paw?owski, Maciej,Newman-Tancredi, Adrian,Kolaczkowski, Marcin
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supporting information
p. 10946 - 10971
(2020/11/09)
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- Delta-aminoalkylbenzofuranol ethers, and preparation method and application thereof
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The invention relates to delta-aminoalkylbenzofuranol ethers represented by chemical structural formula I shown in the description, and an application thereof in the preparation of herbicides. In thechemical structural formula I, R is selected from C1-C2 alkyl groups, and n is selected from 2, 3 and 4.
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Paragraph 0064-0067
(2018/04/01)
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- N-[(dihydrobenzofuran-7-yloxyl)alkyl]-2-aryloxy amide derivatives
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The invention discloses N-[( dihydrobenzofuran-7-yloxyl)alkyl]-2-aryloxy amide derivatives which are represented as a structural formula I and a structural formula II, and in the structural formula I or II, R is selected from a group consisting of H, C1-C2 alkyl, C3-C4 linear alkyl and C3-C4 branched alkyl; n is selected from a group consisting of 1,2,3,4,5 and 6; Y is selected from a group consisting of H, C1-C2 alkyl, F, Cl, Br and I; Y is selected from a group consisting of H, C1-C2 alkyl, F, Cl, Br, I, trifluoromethyl and trifluoroethyl; and Y is selected from a group consisting of H, C1-C2 alkyl, F, Cl, Br and I. The invention also provides an application of the N-[(dihydrobenzofuran-7-yloxyl)alkyl]-2-aryloxy amide derivatives to preparing herbicides.
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Paragraph 0027; 0028; 0029; 0034
(2017/12/27)
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- Towards a new generation of potential antipsychotic agents combining D 2 and 5-HT1A receptor activities
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We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist properties in the same molecule. We describe the structure-a
- Cuisiat, Stephane,Bourdiol, Nathalie,Lacharme, Vincent,Newman-Tancredi, Adrian,Colpaert, Francis,Vacher, Bernard
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p. 865 - 876
(2007/10/03)
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