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

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.