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.

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

“…An extension of the reaction time was not attempted in these cases, since the mass balance indicated significant decomposition of the starting materials. First, a set of four bases (NEt 3 , NaHCO 3 , K 2 CO 3 and NaOAc) and four solvents (MeCN, toluene, THF and DMF) were evaluated (entries [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. While toluene and THF did not facilitate coupling in combination with most bases, the best results were obtained with DMF as the solvent (entries 15-18).…”

Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation

“…This major alkaloid from black pepper was just recently also described by Lee et al to inhibit VSMC migration at a concentration of 100 µM [22]. Piperine and congeners are reported to modulate GABA A receptors and to activate transient receptor potential vanilloid type 1 receptors [33,34]. In pharmacokinetic studies performed in Wistar rats, 1 revealed an absolute oral bioavailability of 24 % [35], and is reported to be a potent bioavailability enhancer for drugs by inhibiting CYP3A4 and human P-glycoprotein [36][37][38][39].…”

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

Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships

“…[19] Investigations carriedout in the small group of Piper capense active ingredients and other synthetic derivatives of piperine led to the conclusion that for sufficient GABA A binding the carbon chain must contain not less than four carbonsa nd at least one double bond, adjacent to the amide group, and the substituent in the amide moiety should be bulky. [91] 9. Regarding the amide moiety,p otency was enhanced by replacing the piperidine with N,N-dibutyl, N,N-diisobutyl, or N,N-bis(trifluoroethyl) groups.…”

“…[116,117] ChemMedChem 2015, 10,1302 -1325 www.chemmedchem.org cinnamamide moiety corresponds to the hydrophobic spacer, and the propers ize required for inhibitory activity was confirmed by molecular modeling studies. Song et al reported the anti-inflammatory activity of panobinostat (91), which suppressedv ariousp ro-inflammatory cytokines. N-Hydroxycinnamamide derivatives acting as HDAC inhibitors were mostly considered as drug candidates for cancer.…”