title: Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives.
abstract: 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%, EC50 = 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 (EC50 = 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 GABAAR modulators.
authors.affiliation: Department of Pharmacology and Toxicology and §Division of Drug Design and Medicinal Chemistry, Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Schöffmann
authors.forename: Laurin
authors.initials: L
authors.lastname: Wimmer
authors.forename: Daria
authors.initials: D
authors.lastname: Goldmann
authors.forename: Sophia
authors.initials: S
authors.lastname: Khom
authors.forename: Juliane
authors.initials: J
authors.lastname: Hintersteiner
authors.forename: Igor
authors.initials: I
authors.lastname: Baburin
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarz
authors.forename: Michael
authors.initials: M
authors.lastname: Hintersteininger
authors.forename: Peter
authors.initials: P
authors.lastname: Pakfeifer
authors.forename: Mouhssin
authors.initials: M
authors.lastname: Oufir
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.forename: Marko D
authors.initials: MD
authors.lastname: Mihovilovic
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D052117:Benzodioxoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000470:Alkaloids; D014151:Anti-Anxiety Agents; D052117:Benzodioxoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011963:Receptors, GABA-A; C008922:piperine