Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives

Author(s)

Angela Schöffmann, Laurin Wimmer, Daria Goldmann, Sophia Khom, Juliane Hintersteiner, Igor Baburin, Thomas Schwarz, Michael Hintersteininger, Peter Pakfeifer, Mouhssin Oufir, Matthias Hamburger, Thomas Erker, Gerhard F. Ecker, Marko D. Mihovilovic, Steffen Hering

Abstract

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABA

_AR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABA

_AR by means of a two-microelectrode voltage-clamp technique. GABA

_AR 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 GABA

_AR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABA

_A (maximal GABA-induced chloride current modulation (I

_GABA-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, I

_GABA-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.

Organisation(s)

External organisation(s)

Technische Universität Wien, Universität Basel

Journal

Journal of Medicinal Chemistry

Volume

57

Pages

5602-5619

No. of pages

18

ISSN

0022-2623

DOI

https://doi.org/10.1021/jm5002277

Publication date

07-2014

Peer reviewed

Yes

Austrian Fields of Science 2012

301406 Neuropharmacology, 301207 Pharmaceutical chemistry

Keywords

ASJC Scopus subject areas

Drug Discovery, Molecular Medicine

Portal url

https://ucrisportal.univie.ac.at/en/publications/65f47a57-68ee-4ad6-a745-eda73e49a091