- Efficient modulation of γ-aminobutyric acid type a receptors by piperine derivatives
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Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure-activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC 50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol- 5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC 50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABA AR modulators.
- Sch?ffmann, Angela,Wimmer, Laurin,Goldmann, Daria,Khom, Sophia,Hintersteiner, Juliane,Baburin, Igor,Schwarz, Thomas,Hintersteininger, Michael,Pakfeifer, Peter,Oufir, Mouhssin,Hamburger, Matthias,Erker, Thomas,Ecker, Gerhard F.,Mihovilovic, Marko D.,Hering, Steffen
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p. 5602 - 5619
(2014/08/05)
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- Synthesis and inhibitory effect of piperine derivates on monoamine oxidase
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A series of piperine derivates (1-19) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. It is worth noting that most of the small amine moieties substituted on the piperidine ring proved to be potent and selective inhibitors of MAO-B rather than of MAO-A. 5-(3,4-methylenedioxyphenyl)-2E,4E-pentadienoic acid n-propyl amide (3) showed the greatest MAO-B inhibitory activity (IC 50(MAO-B) = 0.045 μM) and good selectivity (IC50(MAO-A) = 3.66 μM). The conjugated double bond and carbonyl group of piperine are proved to be an essential feature for piperine and related alkylamides to exhibit MAO-inhibitory activity. Binding mode of the titled compounds was predicted using FlexX algorithm. The design and optimization of novel small molecule monoamine oxidase inhibitors will be guided by the results of this report.
- Mu, Li-Hua,Wang, Bo,Ren, Hao-Yang,Liu, Ping,Guo, Dai-Hong,Wang, Fu-Meng,Bai, Lin,Guo, Yan-Shen
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scheme or table
p. 3343 - 3348
(2012/06/29)
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- NOVEL PIPERINE DERIVATIVES AS GABA-A RECEPTORS MODULATORS
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The present invention encompasses novel piperin compounds of general formula (I) wherein R1, R2, R3, m and n are defined as in claim 1, which are suitable for the prevention and/or treatment of diseases mediated by modulation of GABAA receptor and the use thereof for preparing a medicament having the above mentioned properties.
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Page/Page column 23; 30
(2011/07/30)
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- Toxic effects of natural piperine and its derivatives on epimastigotes and amastigotes of Trypanosoma cruzi
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We describe herein an evaluation of trypanocidal effects of the natural alkaloid piperine and twelve synthetic derivatives against epimastigote and amastigote forms of the protozoan parasite Trypanosoma cruzi, the causative agent of the incurable human disease, Chagas' disease. The results obtained point to piperine as a suitable template for the development of new drugs with trypanocidal activity.
- Ribeiro, Tatiana Santana,Freire-De-Lima, Leonardo,Previato, Jose Osvaldo,Mendonca-Previato, Lucia,Heise, Norton,De Lima, Marco Edilson Freire
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p. 3555 - 3558
(2007/10/03)
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- Effects of piperine analogues on stimulation of melanocyte proliferation and melanocyte differentiation
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A wide range of piperine analogues has been synthesised in order to undertake a structure-activity study of their ability to stimulate melanocyte proliferation. Results demonstrate that an aromatic ring containing at least one ether function and a carbonyl group containing side chain is essential for this activity. A number of highly active piperine analogues have been identified, for instance 1-(3,4-methylenedioxyphenyl)-penta-2E,4E-dienoic acid methyl ester (5a), 1-E,E-piperinoyl-isobutylamine (4f) and 1-(3,4- methylenedioxyphenyl)-pentanoic acid cyclohexyl amide (20). A selection of analogues has also been evaluated for their effect on melanocyte morphology and melanogenesis. The piperine analogues altered cell morphology by increasing dendrite formation leading to bi-, tri- and quadripolar cells. These same analogues were found to increase total melanin in cell cultures, although melanin content per cell was not significantly altered from control in the presence of these compounds.
- Venkatasamy, Radhakrishnan,Faas, Laura,Young, Antony R.,Raman, Amala,Hider, Robert C.
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p. 1905 - 1920
(2007/10/03)
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- Is a nitrogen atom an important pharmacophoric element in sigma ligand binding?
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A lingering question in σ receptor ligand development is whether a nitrogen atom serves as an important pharmacophoric element in binding affinity. To address this question, we have synthesized several phenylalkylpiperidines and phenylalkylpiperazines and
- Ablordeppey, Seth Y.,Fischer, James B.,Glennon, Richard A.
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p. 2105 - 2111
(2007/10/03)
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