Developing piperine towards TRPV1 and GABA<sub>A</sub> receptor ligands – synthesis of piperine analogs via Heck-coupling of conjugated dienes

Wimmer, Laurin; Schönbauer, David; Pakfeifer, Peter; Schöffmann, Angela; Khom, Sophia; Hering, Steffen; Mihovilovic, Marko D.

doi:10.1039/c4ob02242d

Cited by 14 publications

(15 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the compound concomitantly activates TRPV1 receptors [4], which is undesirable for a lead structure as unwanted side effects might possibly occur. A large series of semisynthetic and fully synthetic piperine analogs was therefore synthesized, with the objective to obtain compounds with improved GABAA receptor activity and reduced TRPV1 receptor interaction [2,7,9]. Among these, the analogs SCT-66, SCT-64, SCT-29, LAU397, and LAU399 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…penta-2,4-dienamide (LAU397; compound 6 in reference [9]), and (2E,4E)-N,N-dibutyl-5-(thiophen-3-yl)penta-2,4-dienamide (LAU399; compound 16 in reference [9]) were synthesized at TU Wien as described elsewhere [2,7,9]. Piperine, Tween 20, bovine serum albumin (BSA), Dulbecco's Modified Eagle Medium (DMEM) high glucose, and sodium fluorescein (Na-F) were purchased from Sigma-Aldrich (Steinheim, Germany).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…However, all compounds synthesized up to that point contained the metabolically liable 1,3benzodioxole group [8]. Hence, a set of 15 aryl-modified piperine analogs was synthesized bearing the nonnatural dibutylamide function [9]. Of these, the analogs LAU397 and LAU399 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Of these, the analogs LAU397 and LAU399 ( Fig. 1) were significantly more efficient at the GABAA receptor than piperine while being devoid of in vitro TRPV1 receptor interaction [9].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In vitro blood–brain barrier permeability predictions for GABAA receptor modulating piperine analogs

Eigenmann

Dürig

Jähne

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

Self Cite

View full text Add to dashboard Cite

The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Chemicals and Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Of these, the analogs LAU397 and LAU399 ( Fig. 1) were significantly more efficient at the GABAA receptor than piperine while being devoid of in vitro TRPV1 receptor interaction [9].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In vitro blood–brain barrier permeability predictions for GABAA receptor modulating piperine analogs

Eigenmann

Dürig

Jähne

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have previously reported the synthesis of compounds 14 [41] and 15-25 [33] including procedures in full experimental detail (l " Fig. 5).…”

Section: Synthesis Of Piperine Analogsmentioning

confidence: 99%

Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation

Mair

Atanasov

et al. 2015

Planta Med

Self Cite

View full text Add to dashboard Cite

Successful vascular healing after percutaneous coronary interventions is related to the inhibition of abnormal vascular smooth muscle cell proliferation and efficient re-endothelialization. In the search for vascular smooth muscle cell anti-proliferative agents from natural sources we identified piperine (1), the main pungent constituent of the fruits from Piper nigrum (black pepper). Piperine inhibited vascular smooth muscle cell proliferation with an IC50 of 21.6 µM, as quantified by a resazurin conversion assay. Investigations of ten piperamides isolated from black pepper fruits and 15 synthesized piperine derivatives resulted in the identification of three potent vascular smooth muscle cell proliferation inhibitors: the natural alkaloid pipertipine (4), and the two synthetic derivatives (2E,4E)-N,N-dibutyl-5-(3,5-dimethoxyphenyl)penta-2,4-dienamide (14) and (E)-N,N-dibutyl-3-(naphtho[2,3-d][1,3]dioxol-5-yl)acrylamide (20). They showed IC50 values of 3.38, 6.00, and 7.85 µM, respectively. Furthermore, the synthetic compound (2E,4E)-5-(4-fluorophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (12) was found to be cell type selective, by inhibiting vascular smooth muscle cell proliferation with an IC50 of 11.8 µM without influencing the growth of human endothelial cells.

show abstract

Validation of an immortalized human (hBMEC) in vitro blood-brain barrier model

et al. 2016

View full text Add to dashboard Cite

We recently established and optimized an immortalized human in vitro blood-brain barrier (BBB) model based on the hBMEC cell line. In the present work, we validated this mono-culture 24-well model with a representative series of drug substances which are known to cross or not to cross the BBB. For each individual compound, a quantitative UHPLC-MS/MS method in Ringer HEPES buffer was developed and validated according to current regulatory guidelines, with respect to selectivity, precision, and reliability. Various biological and analytical challenges were met during method validation, highlighting the importance of careful method development. The positive controls antipyrine, caffeine, diazepam, and propranolol showed mean endothelial permeability coefficients (P e) in the range of 17-70 × 10(-6) cm/s, indicating moderate to high BBB permeability when compared to the barrier integrity marker sodium fluorescein (mean P e 3-5 × 10(-6) cm/s). The negative controls atenolol, cimetidine, and vinblastine showed mean P e values < 10 × 10(-6) cm/s, suggesting low permeability. In silico calculations were in agreement with in vitro data. With the exception of quinidine (P-glycoprotein inhibitor and substrate), BBB permeability of all control compounds was correctly predicted by this new, easy, and fast to set up human in vitro BBB model. Addition of retinoic acid and puromycin did not increase transendothelial electrical resistance (TEER) values of the BBB model.

show abstract

Developing piperine towards TRPV1 and GABA_A receptor ligands – synthesis of piperine analogs via Heck-coupling of conjugated dienes

Cited by 14 publications

References 29 publications

In vitro blood–brain barrier permeability predictions for GABAA receptor modulating piperine analogs

In vitro blood–brain barrier permeability predictions for GABAA receptor modulating piperine analogs

Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation

Validation of an immortalized human (hBMEC) in vitro blood-brain barrier model

Contact Info

Product

Resources

About

Developing piperine towards TRPV1 and GABAA receptor ligands – synthesis of piperine analogs via Heck-coupling of conjugated dienes

Cited by 14 publications

References 29 publications

In vitro blood–brain barrier permeability predictions for GABAA receptor modulating piperine analogs

In vitro blood–brain barrier permeability predictions for GABAA receptor modulating piperine analogs

Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation

Validation of an immortalized human (hBMEC) in vitro blood-brain barrier model

Contact Info

Product

Resources

About

Developing piperine towards TRPV1 and GABA_A receptor ligands – synthesis of piperine analogs via Heck-coupling of conjugated dienes