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Figure 1. Piperine
molecule can be structurally divided into three moieties:
the 1,3-benzodioxole or aromatic function, the linker region comprising
four carbon atoms, and the amide function natively constituted by
a piperidine ring.
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Scheme 1. Structural Modifications of the Piperine
Scaffold
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Scheme 2. Synthesis of Piperine
Derivatives with Modification of the Amide
Function and Truncated Alkene SpacerConditions: (a) Amine (3.5
equiv), dry THF, rt. (b) Lawesson’s reagent, dry THF, rt. (c)
LiAlH4, THF, rt.
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Figure 2. (A, B) Modulation of
chloride currents through GABAA receptors composed of α1, β2,
and γ2S subunits by 100 μM piperine and the
indicated derivatives (dotted line indicates cutoff for highly active
compounds). (C, D) Concentration-dependent IGABA (EC3–7) enhancement through α1β2γ2S GABAA receptors,
(C) for 22 (▲), 23 (●), 25 (◆), and 35 (■), ranked by efficiency,
and (D) for 25 (○) and 43 (●), ranked by potency, compared to piperine (dotted line).
(E, F) Representative IGABA modulated
by (E) 23 and (F) 25. Data represent mean
± SEM from at least three oocytes and two oocyte batches. Asterisks
indicate statistically significant differences from zero: *p < 0.05, **p < 0.01. Data for piperine
were taken from ref (31).
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Scheme 3. Synthesis of Piperine Analogues Containing
an Aryl SpacerConditions: (d) Boronic acid,
Pd(PPh3)4 2 mol %, K2CO3, DME/EtOH/water, 140 °C, mw, 1 h. (e) Either (COCl)2, cat. DMF, and DCM or EDCI·HCl, HOBt, and dry DCM, followed
by amine.
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Scheme 4. Synthesis
of Piperine Analogues with (Partial) Integration of the
Spacer Motif into an Aryl CoreConditions: (e) Either (COCl)2, cat. DMF, and DCM or EDCI·HCl,
HOBt, and dry DCM, followed
by amine. (f) CO, Pd(OAc)2, dppp, Hünig’s
base, DMF/water, 70 °C. (g) Methyl acrylate, Pd(OAc)2 5 mol %, phenanthroline monohydrate 5.5 mol %, NEt3,
dry DMF. (h) LiOH, THF/water, rt. (i) B2pin2, [Ir(OMe)cod]2 1.5 mol %, 4,4′-di-tert-butyl-2,2′-bipyridine 3 mol %, cyclohexane, reflux. (j) CuBr2, MeOH/water. (k) Methyl acrylate, Pd(OAc)2 3 mol
%, (o-tolyl)3P 6 mol %, NEt3, 80 °C. (l) Methyl acrylate, NaI, dry DMF, 90°C. (m) DDQ,
benzene, 80 °C.
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Figure 3. (A, B) Modulation of chloride currents through GABAA receptors composed of α1, β2,
and γ2S subunits by 100 μM piperine and the
indicated derivatives (dotted line indicates cutoff for highly active
compounds). (C, D) Concentration-dependent IGABA (EC3–7) enhancement through α1β2γ2S GABAA receptors:
(C) by 47 (■), 53 (▲), and 72 (●), ranked by efficiency, and (D) by 56 (▲) and 73 (●), ranked by potency, compared
to piperine (dotted line). (E, F) Representative IGABA modulated by (E) 72 and (F) 73. Data represent mean ± SEM from at least three oocytes and
two oocyte batches. Asterisks indicate statistically significant differences
from zero: *p < 0.05, **p <
0.01. Data for piperine were taken from ref (31).
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Figure 4. Analysis
of subunit preferential IGABA enhancement
by (A, B) the most efficient (23) and (C,
D) the most potent (25) piperine derivatives. (E, F)
Representative IGABA through seven GABAA receptor subtypes by 23 at 100 μM. Data
represent mean ± SEM from at least three oocytes and two oocyte
batches.
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Figure 5. Relation between log(potentiation of IGABA) of dialkyl-substituted piperine derivatives
at the amide nitrogen
and number of carbon atoms at this region. Data for 24* were taken from ref (34).
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Figure 6. Decision tree obtained
for the data set of 76 piperine derivatives
with PHYSCHEM descriptor set.
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Figure 7. Decision tree obtained for the data set of 76 piperine
derivatives
with MACCS fingerprints.
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Figure 8. Compounds 23 and 25 display anxiolytic
effects in the EPM test and little sedation in the OF test. Bars indicate
time spent in open arms (OA) as a percentage of the total time 30
min after ip application of the indicated dose (in milligrams per
kilogram of body weight) of (A) 23 and (B) 25 and the total ambulation after application of (C) 23 and (D) 25. White bars illustrate the behavior of control
mice. Bars represent means ± SEM from at least eight different
mice. Asterisks indicate statistically significant differences to
control *p < 0.05, **p < 0.01
[analysis of variance (ANOVA) with Bonferroni]. Shaded bars for the
behavioral effects of piperine are taken from ref (34). Behavioral experiments
comparing the sedative and anxiolytic potential of piperine, 23, and 25 have been conducted in parallel.
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