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The Structure and Ion Channel Activity of 6-Benzylamino-3-hydroxyhexa-cyclo[6.5.0.03 7.04 12.05 10.09 13]tridecane

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Arch. Pharm. Pharm. Med. Chem. 2003, 2, 127–133
a
b
c
d
Pharmaceutical Chemistry,
Potchefstroom University for
Christian Higher Education,
Potchefstroom, South Africa
Department of Physiology,
Potchefstroom University for
Christian Higher Education,
Potchefstroom, South Africa
Department of Physiology,
University of Pretoria,
Pretoria, South Africa
Department of
Pharmaceutical Sciences,
School of Pharmacy, Texas
Tech University Health
Sciences Center, Amarillo,
TX 79106, USA
The Structure and Ion Channel Activity of
6-Benzylamino-3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13]tridecane
A novel compound, 6-benzylamino-3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13]tridecane, was synthesized as part of an ongoing study to explore the ion channel
activity of polycyclic cage amines. The known polycyclic calcium channel antagonist, 8-benzylamino-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane (NGP 1-01)
served as the lead compound and as a positive control for channel activity. The title
compound inhibited calcium currents at test concentrations of 10 µM at depolarized
membrane potentials (in the potential range where the L-type calcium channel inactivates). At the test concentrations modulating effects were also observed for sodium and the delayed rectifier potassium currents. Due to its activity at both Ca2+ and
Na+ channels, this compound may offer utility as a cardiovascular and/or neuroprotecting agent.
Keywords: 6-Benzylamino-3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13]tridecane;
Ion channel; Polycyclic amine
Received: July 1, 2002 [FP710]
Introduction
Several polycyclic amines have been reported to exhibit
activity on the voltage dependent L-type calcium channel in cardiac myocytes [1]. In earlier work by us, potassium and sodium channels were excluded from the pool
of conducting channels studied by blocking potassium
channels with appropriate channel blockers and using
membrane potentials where sodium channels were
inactivated [2]. The aim of the present study was to investigate the activity of a novel polycyclic “cage” amine
on calcium, sodium and potassium channels. 8-Benzylamino-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane
(NGP 1-01, Figure 1) [3,4] is structurally unrelated to
any of the known calcium antagonists but was found to
inhibit calcium current of L-type calcium channels in cardiac cells [5, 6]. Increasing evidence suggests that abnormalities in specific ion channels – including L-type
calcium, delayed rectifier potassium and sodium channels – play an important role in the configuration and duration of the cardiac action potential under pathophysiological conditions [7]. Ion channels are important for cellular homeostasis and serve to conduct ions across cell
membranes in response to a variety of chemical or physCorrespondence: Sarel F. Malan, Pharmaceutical Chemistry,
Potchefstroom University for Christian Higher Education,
Private Bag X6001, Potchefstroom, 2520, South Africa. Phone:
+27 18 2992266, fax: +27 18 2992284, e-mail: fchsfm@puknet.
puk.ac.za.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ical stimuli. It therefore acts as cellular effectors through
which information received at receptors is transduced into response [8].Voltage gated ion channels are of particular interest because they are critical to the functioning
of many excitable systems including axonal conduction,
neural firing, and excitation-contraction coupling [8–11].
It is now also accepted that a disruption of intracellular
Ca2+ homeostasis is associated with the early development of cell injury [12–14]. A large number of studies report that the calcium ion plays a critical role in cytotoxicity
and cell death in many tissues [15]. Evidence has also
been accumulating that the calcium ion plays a critical
role in toxic neuronal cell death and apoptosis in brain
and spinal tissue [16, 17]. Recent research has established some of the biochemical mechanisms by which intracellular Ca2+ overload can trigger either necrotic or
apoptic cell death [18] and a number of studies have
shown that prevention of Ca2+ overload by pre-treatment
with Ca2+ channel blockers can rescue cells that would
otherwise die [19].
Figure 1. 8-Benzylamino-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane (NGP 1-01)
0365-6233/02/0127 $ 17.50+.50/0
Full Paper
Sarel F. Malana,
Karin Dyasonb,
Bianca Wagenaarc,
J. Jurgens van der Waltb,
Cornelis J. Van der Schyfa,d
6-Benzylamino-3-hydroxyhexacyclotridecane 127
128 Malan et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 127–133
Figure 2. Synthesis of 6-benzylamino-3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13]tridecane (1) [2]
Disturbance in the intracellular homeostasis – especially
calcium overload in heart muscle during reperfusion injury – is also the main cause of cell death after coronary
infarction. However, in this case blocking of L-type calcium channels does not prevent damage but blocking of
the fast TTX-sensitive sodium channels does [20]. In
heart and nerve tissue, blocking the inward rectifier potassium channel would be counterproductive as it would
lead to depolarization, while blocking the delayed rectifier potassium channels would have a useful anti-arrhythmic influence in the heart as it would prolong the duration
of the action potential and the refractory period. In the
central nervous system, blocking of potassium channels
may potentiate memory [21]. Due to these considerations and others, the properties of ion channel active
polycyclic amines should be critically evaluated on different channels by measuring a variety of electrophysiological properties.
Van der Schyf et al. [5] postulated that the pentacycloundecane skeleton might serve only as a bulk contributor to
the activity of NGP 1-01. In the current report, the polycyclic moiety of the molecule was therefore modified by
introducing the polycycle, 3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13]tridecane.This polycyclic “cage”
was obtained by the boron trifluoride etherate promoted
reaction of pentacyclo[5.4.0.02,6.03,10 .05,9 ]undecane8,11-dione with ethyl diazoacetate [22] followed by
subsequent
decarbalkoxylation
[23]. Reductive
amination of this hydroxyketone with benzylamine rendered 6-benzylamino-3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13]tridecane (1) (Figure 2) [2].
Results and discussion
Synthesis
High-resolution mass spectrometry showed the empirical formula of 1 to be C20H23NO (calculated: 292.1701;
experimental: 292.1701). The structure was confirmed
by IR, NMR, and MS.
Figure 3. 6-Benzylamino-3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13]tridecane (1).
Physical data for C20H23NO: mp 123 °C; IR (KBr): ν =
3300 (OH), 3145 (NH), 2950 (CH), 1485 (C=C) cm–1; 1 H
NMR (CDCl3): δ = 7.33 (m, 5 H, H-18, 19, 20, 21, 22),
3.82 (AB-q, 2 H, J = 12.88 Hz, H-16a, 16b), 3.37 (t, 1 H, J
= 3.36 Hz, H-6), 2.72 (dd, 1 H, J = 3.02 Hz, H-8), 2.66 (t,
1 H, J = 6.04 Hz, H-1), 2.49 (m, 2 H. H-5, 12), 2.36 (m,
3 H, H-4, 9, 13), 2.17 (d, 1 H, J = 5.43 Hz, H-10), 1.99 (m,
1 H, H-7), 1.64 (AB-q, 2 H, J = 11.33 Hz, H-2), 1.30
(AB-q, 2 H, J = 9.61 Hz, H-11); 13C NMR (CDCl3): δ =
140.97 (s, C-17), 128.61 (d, C-18, 22), 128.44 (d, C-19,
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 127–133
6-Benzylamino-3-hydroxyhexacyclotridecane 129
21), 127.11 (d, C-20), 85.20 (s, C-3), 55.59 (d, C-6),
52.85 (t, C-16), 51.16 (d, C-4), 50.88 (d, C-7), 47.64 (d,
C-5), 42.25 (d, C-9/13), 40.85 (t, C-11), 38.86 (d, C-12),
38.52 (t, C-2), 37.32 (d, C-10), 35.25 (d, C-8), 32.92 (d,
C-1), 31.94 (d, C-9/13); MS (70 eV): m/z (%) = 292 (12)
[M+ – H], 274 (6) [M+ – H3O], 202 (36) [M+ – CH2C6H5],
186 (25) [M+ – NH2CH2C6H5], 149 (19), 106 (19), 91
(100), 69 (65).
28.75 ± 4.33 % (n = 6).This blocking effect was reversible
and the inhibition of the calcium current compared favorably with that of the reference compound (NGP 1-01;
19.2 ± 5.4 % [2, 24]) at an identical concentration.
Electrophysiology
Effect on L-type calcium channels
At a holding potential of –40 mV and a test potential of
10 mV, 10 µM of 1 blocked the calcium channel by
Voltage dependence of L-type calcium channel inhibition
Inhibition of the L-type calcium current was found to be
voltage dependent with greater effect at depolarized
membrane potentials (Figure 4). At a membrane potential of –50 mV a minor tonic inhibition is obtained while at
–25 mV approximately 58 % (n = 3) of the available
channels are inhibited. Relative inhibition increases with
depolarization in the range of membrane potentials
where calcium channels inactivate which suggests that
1 blocks the calcium channel in the inactivated state or
that the voltage dependence of inactivation is changed
by this compound, both scenarios leading to inhibition of
the calcium current. Boltzmann fitting of the activation
and inactivation parameters obtained in the presence of
10 µM of 1 showed that the voltage dependence of activation was not affected (Figure 5A). The voltage dependence of inactivation (Figure 5B) was shifted to
more negative membrane potentials (–4.5 mV; n = 3;
p < 0.05) while the slope factor was not influenced significantly.
Effect on T-type calcium channels
Figure 4. Relative inhibition of the L-type calcium current
obtained with 10 µM of 1 at different holding potentials.
Maximum relative inhibition was 61.3 ± 1.3 % at –28 ±
1.5 mV (n = 3).
At a holding potential of –90 mV the current was clamped
for 100 ms to test potentials ranging between –60 mV
and 25 mV. Currents in the potential range where the Ttype channel activates (–50 mV to –20 mV) were not significantly affected (Figure 6). Due to the hyperpolarized
Figure 5. Effect of 1 (10 µM) on the voltage dependence of activation (A) and inactivation (B) of the L-type calcium
channel. In the inactivation curve (B) the membrane potential for 50 % inactivation (V½) is shifted from –30.8 mV under
control conditions to –35.3 mV in the presence of 1. The slope factors were 2.98 mV for controls and 3.5 mV in the
presence of 10 µM of 1.
130 Malan et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 127–133
holding potential (–90 mV) the effect of 1 (50 µM) on the
L-type channels (0 to +20 mV) was less (19 % at 10 mV)
than that observed with a 10 µM test concentration at a
holding potential of –40 mV (29 % at 10 mV).
From these data it is clear that 1, at a concentration of
50 µM, has a selective effect on the L-type calcium
channel in cardiac myocytes.
Effect on sodium channels
Figure 6. Influence of 1 (50 µM) on calcium currents in
the potential range where T-type and L-type calcium
channels activate (at –50 to –20 mV and 0 to +20 mV respectively).
Concentrations of 10, 20, and 50 µM were used to obtain
the concentration response relation for 1. The title compound (1) showed 50 % sodium channel inhibition (IC50)
at a concentration of 12.5 ± 2.7 µM (n = 6). The slope
factor of the curve was 1 suggesting a 1 to 1 stoichiometry between the compound and the channel receptor. At
a test concentration of 20 µM 1 showed 68 % inhibition
Figure 7. (A) Current-voltage relationship of sodium currents in the presence of 50 µM of 1 and control experiments. (B)
Steady-state activation with 50 µM of 1. (C) Influence of 1 on the inactivation of the sodium channel (see text for description).
Figure 8. Delayed rectifier potassium currents in control (A); in the presence of 20 µM of 1 (B); during washout (C); after
application of 300 µM sotalol (D); in the presence of 300 µM sotalol and 20 µM of 1 (E).
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 127–133
6-Benzylamino-3-hydroxyhexacyclotridecane 131
of the peak sodium current (–40 mV) and the highest
test concentration (50 µM) caused the peak inward sodium current to decrease by approximately 80 %
(Figure 7A). At this concentration (50 µM), 1 had no significant effect on the voltage dependency of steady-state
activation of the sodium channel (Figure 7B) but shifted
the voltage dependency of inactivation to more negative
membrane potentials (V½ shifted from –90.23 mV to
–95.10 mV; n = 7; p < 0.05), thereby decreasing the sodium current (Figure 7C). The slope factor was not influenced.
component of the delayed rectifier current (IKr), was added (Figure 8D).The current remaining in the presence of
300 µM sotalol represented the slow component of the
delayed rectifier potassium current (IKs). Application of
20 µM of 1 had no additional effect on this remaining current (Figure 8E).
Effect on the inward and delayed rectifier potassium
channels
Compound 1 was tested on the inward (IK1) and delayed
rectifier (IK) potassium currents in cardiac myocytes.The
delayed rectifier current contributes to the repolarization
phase of the cardiac action potential and consists of two
distinct current components (IKr : rapid activating and IKs:
slow activating) [25]. Small changes in IK conductance
may lead to significant changes in the duration of the cardiac action potential [26]. At a concentration of 20 µM, 1
had no effect on the inward rectifier potassium current
(IK1), but a prominent effect was observed on the delayed
rectifier potassium currents (Figure 8). Upon depolarization of the membrane the delayed rectifier potassium
channels activate and the outward current increases as
the test potential becomes more positive. Deactivating
tail currents were observed at –40 mV, between 225 and
900 ms. After application of 1 the peak delayed rectifier
tail current (at 50 mV) was blocked by approximately
40 % (Figure 8B), this effect being completely reversible
(Figure 8C). To investigate the selectivity of 1 towards
the two components of the delayed rectifier potassium
current (IKr and IKs) sotalol, a selective blocker of the fast
Figure 9. Current-voltage relationship of the deactivating tail currents shown in Figure 8.
For the current voltage relationship (Figure 9) the peak
values of the tail currents (Figure 8) were plotted as a
function of the test potential. From this result it is clear
that 1 blocks the fast component of the delayed rectifier
(IKr) over the whole voltage range of test potentials with
no significant effect on the slow component (IKs)
(Figure 9). Similar results were seen with members of
the class III anti-arrhythmic agents like sotalol, dofetilide
and E-4031 [27].
Conclusion
The experimental data show that the title compound has
little selectivity towards the ion channels investigated in
cardiac muscle of the guinea pig. At test concentrations
of 10–50 µM, inhibition of ion currents was observed for
L-type calcium channels, sodium channels and the fast
component of the delayed rectifier potassium channel.
However, no effects were observed for T-type calcium
channels or for the inward rectifier and slow component
of the delayed rectifier potassium channels. The slope
factors for 1 obtained from curve fitting suggest that a
stoichiometric relationship of compound to receptor exists in all the above cases of activity.These observations
exclude the possibility of a non-selective interaction with
the membrane, an event that is likely to change the function of all channels. The current results, together with
earlier observations [2, 28] suggest that the activity profiles on ion channels elicited by these polycyclic amines
can be effectively manipulated through structural modification.This was demonstrated by side-chain substitution
of NGP 1-01 to derive a series of compounds that
showed structure-related modulation of the action of
these derivatives on the L-type calcium channel [2, 28].
These findings suggest that the ion channel selectivity
profile of 1 likely can be changed through chemical modification. The promiscuous inhibitory ion channel activity
on both potassium and calcium channels demonstrated
by 1 may be of significant clinical relevance. Recently, it
has been suggested that combining potassium and calcium channel blocking mechanisms reduces the proarrhythmic potential of selective class III antiarrhythmic
agents in the treatment of cardiac arrhythmias [29, 30].
One such compound, BRL-32872 {N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl)ethyl]propyl]-4nitrobenzamide hydrochloride} is a typical example of an
antiarrhythmic agent with combined potassium and cal-
132 Malan et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 127–133
cium blocking actions and has been reported to be effective in reducing the incidence of proarrhythmias in antiarrhythmic treatment regimens [30, 31]. Antagonists of
both sodium and calcium channels such as CNS 1237
(N-acenaphthyl-N⬘-4-methoxynaphth-1-yl guanidine)
[22] are reported to be significant neuroprotective
agents [33], and amiodarone – commonly used for drug
resistant arrhythmias [34] – has various properties including potassium, sodium, calcium, and non-specific
sympathetic blocking effects when it is given orally [35].
night with sodium borohydride (1 g, 26 mmol) in dry methanol
(10 mL) and dry THF (50 mL). The solvent was removed and
water added. Extraction with dichloromethane (4 × 50 mL),
evaporation of the solvent and recrystallization from
hexane rendered 6-benzylamino-3-hydroxyhexacyclo[6.5.0.0.3,7.04,12.05,10.09,13]tridecane (1) as a white crystalline
solid (yield: 0.86 g; 84.3 %).
Acknowledgement
We thank Dr. J.M. van Rooyen and Mr. M.N. van Aarde for
their assistance in the recording of Ca2+ channel data,
Mrs.C.M.T.Fourie for the isolation of myocytes and Dr.L.
Fourie and Mr. J.A. Joubert for recording of mass and
NMR spectra, respectively.
Experimental
Synthesis
Pentacyclo[5.4.0.0 2,6 .0 3,10 .05,9 ]undecane-8,11-dione (6 g,
34.5 mmol) was dissolved in dry diethyl ether (200 mL) and
cooled to –78 °C in dry ice and acetone. Boron trifluoride etherate (19 g, 138 mmol) was slowly added over 10 min while stirring. To this mixture ethyl diazoacetate (7.9 g, 69 mmol) was
added dropwise so as to evolve a slow but constant flow of nitrogen while the reaction mixture was stirred for 1 h. The temperature was increased to –21 °C and stirring continued for another hour. The mixture was then left to reach room temperature and poured into a separating funnel filled with water
(500 mL).The layers were separated and the ether fraction was
successively washed with 10 % sodium bicarbonate (2 ×
200 mL) and water (2 × 200 mL), dried over magnesium sulfate, and evaporated under reduced pressure at 45–50 °C. The
product was a solid suspended in oil. After filtration and recrystallization from 20 % ether-hexane, the dicarboxylate was obtained as colorless needles (2.4 g, 7 mmol). A mixture of this
dicarboxylate, sodium chloride (0.78 g), DMSO (52 mL), and
water (2.6 mL) was allowed to reflux (165 °C) under nitrogen
for 4 h. The mixture was poured onto ice water and extracted
with dichloromethane (3 × 50 mL). The organic fraction was
washed with water, dried over magnesium sulfate, and
evaporated to a white solid. Recrystallization from acetonehexane
yielded
the
product,
3-hydroxyhexacyclo[6.5.0.0.3,7.04,12.05,10.09,13]tridecan-6-one as a white crystalline
solid (yield: 1.34 g; 6.6 mmol; 19.2 %).The physical data of this
product corresponded with those described in the
literature [22].
3-Hydroxyhexacyclo[6.5.0.0.3,7.04,12.05,10.09,13]tridecan-6-one
(0.7 g, 3.5 mmol, prepared above) was dissolved in THF
(20 mL) and benzylamine (0.4 g, 3.5 mmol) was slowly added
under stirring. The solution turned milky and after 3 h the solvent was removed to give a white residue, which was dehydrated under Dean-Stark conditions with dry benzene. Evaporation
left the Schiff base as an oil, which, in turn, was reduced over-
Electrophysiology
Whole cell clamping
The study protocol was approved by the Animal Experimentation Ethics Committee of the Potchefstroom University for CHE
and conforms to the NIH guidelines for animal research.
Ventricular myocytes from the hearts of Duncan-Hartley strain
guinea pig were isolated by enzymatic dispersion of the cells
with collagenase and protease on a Langendorff apparatus as
previously described by Mitra and Morad [36] and modified by
Tytgat [37]. Male/female guinea pigs (300–350 g) were obtained from the Laboratory Animal Center at the Potchefstroom
University.The guinea pigs were anesthetized with pentobarbitone before removing the heart.
A Dagan1 amplifier was used for patch clamping and electrodes
were made from borosilicate glass using a Narishige PP 83model puller. Electrodes (2–3 mΩ) were heat polished before
seal formation. A GΩ seal was formed by light suction. The
patch was ruptured and 15 min were allowed for internal dialysis to reach equilibrium. Voltage clamping was done using the
chopped clamp method [38]. A multibarrel superfusion system
with micro valves, which allowed changes in the bath solutions
in less than 1 second, was used. The pclamp 5.5® program
Axon Instruments Inc., 1989) was used to control the experiments and to store the acquired data.
A stabile control current was used and significant change in the
current and reversibility of this effect with washout was considered as real.
The usual composition of the Tyrode solution for superfusion
was (mM): KCl 5.4; CaCl2 1.8; CsCl 20; MgCl2 0.5; NaCl 137.6;
glucose 5 and HEPES-NaOH 11.6 (pH = 7.4).The pipette solution was (mM): MgCl2 5; Na2ATP 5; HEPES 10; CsCl 125; EGTA
15; TEA-Cl 20 and NaOH to pH = 7.2.
Calcium channel (L-type)
Calcium currents were measured as the maximum inward current after subtraction of background currents. A test concentration of 10 µM was used and activity was expressed as the percentage of inhibition of the calcium current as registered before
addition of 1. Potassium currents were eliminated by the presence of CsCl (20 mM) in the Tyrode and TEA-Cl to the pipette
solution and the effects of sodium channels by pre-clamping at
–35 mV.The steady-state activation parameters for the calcium
channel was determined by voltage clamping from a holding
potential of –35 mV to test potentials between –30 and +30 mV
for 400 ms. From the current-voltage relation for the calcium
channel, the activation parameters were obtained by curve fitting using a Boltzman equation.These parameters describe the
potential dependence of the channel in the activated or open
state. Steady-state inactivation curves were obtained by
clamping from conditioning potentials between –50 to –20 mV
for 25 ms to a test potential of +10 mV. Voltage dependence of
1
Dagan, Model 8800 Total clamp.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 127–133
6-Benzylamino-3-hydroxyhexacyclotridecane 133
channel inhibition was obtained by voltage clamping from a
holding potential of –35 mV to test potentials at intervals of 8 s
with 5 mV steps up to +30 mV.The degree of inhibition at different membrane potentials was expressed as the relative inhibition which is ICa(control)–ICa(drug)/ICa(control) × 100. The
membrane potential of maximal channel inhibition could be obtained from the graph of relative inhibition vs. conditioning potential. For all experiments mean values were calculated from
experiments on different cells from separate heart preparations.
[7] D. M. Roden, A. L. George, Am. J. Physiol. 1997, 273,
511–525.
Calcium channel (T-type)
For this series of experiments a holding potential of –90 mV
and test potentials of between –60 and +25 mV with a duration
of 100 ms were used. A 5.4 mM calcium Tyrode solution (pH =
7.4) to increase the T-currents and 50 µM of test compound
was used. The higher test concentration was necessary because of the high holding potential (–90 mV). With this procedure both T- and L-currents were recorded. The T-current could
be separated from the L-current as the component that peaked
between –40 and –20 mV in the current-voltage relation.
Sodium channel
NiCl2 (5 mM) or CoCl2 (5 mM) and CsCl (20 mM) were added
to the Tyrode solution (pH = 7.4) to eliminate the calcium and
potassium currents respectively. Test concentrations of 10, 20,
and 50 µM were used.To evaluate the effect of 1 on inactivation
of the sodium channel, conditioning potentials of –110 to
–65 mV and a test potential of –30 mV were used. The effect
on the current-voltage relationship was obtained using a holding potential of –100 mV and test potentials of –70 to –30 mV
(in 5 mV steps). From the current-voltage relation, the steadystate activation parameters were obtained by curve fitting using
a Boltzmann equation.
Potassium channel
For the effect of 1 on IK1 (the inward rectifier), a holding potential
of –80 mV and test potentials of –150 to –40 mV (10 mV steps)
were used. For the delayed rectifiers (IKr and IKs) a holding potential of –40 mV and test potentials of –30 to +50 mV were
used. The calcium current was effectively blocked by adding
CdCl2 (100 µM) to the Tyrode solution (pH = 7.4). Test concentrations of 20 µM were used. 300 µM Sotalol, a selective blocker of IKr, was used to investigate the selectivity of 1 towards the
two components of the delayed rectifier potassium current.
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Tobacco, coffee,
and other poisons
Manfred Hesse
Alkaloids
Nature´s Curse or Blessing?
Contents:
PART A: CHEMICAL ASPECTS
Introduction / Classification of Alkaloids / Structural
Analysis / Artefacts / Chiroptical Properties / Synthesis
PART B: BIOLOGICAL ASPECTS
Chemotaxonomy / Aspects of Biogenesis / Importance of
Alkaloids for their Producers and Owners
47323025_ba
PART C: HISTORICAL ASPECTS
Chemistry of Alkaloids / Cultural History and Active
Principles of Selected Alkaloids
2002. 414 pages, 185 images, 110 in color. Hardcover.
e 129.–* / sFr 190.– / £ 75.–
ISBN 3-906390-24-1
*The e-Price is valid only for Germany.
Alkaloids, nitrogen-containing natural substances produced by plants, animals, and microorganisms, have been captivating and fascinating mankind from ancient times because of
their varied and often strong physiological effects. Typical and well-known alkaloids include,
for example, cocaine, heroin, strychnine, curarine, and caffeine.
With its focus on structures and syntheses this book also covers the biological, biosynthetic, and
pharmacological aspects of alkaloids. A chapter detailing the cultural and historical significance
of the most important agents completes this unique compendium.
Wiley-VCH, Customer Service Department, P.O. Box 10 11 61 ,
D-69451 Weinheim, Germany, Fax +49 (0) 6201 606-184,
e-mail: service@wiley-vch.de, www.wiley-vch.de
John Wiley & Sons, Ltd., Customer Services Department,
1 Oldlands Way, Bognor Regis, West Sussex, PO22 9SA England,
Fax: +44 (0) 1243-843-296, www.wileyeurope.com
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channel, structure, ion, benzylamine, activity, cycle, tridecane, hydroxyhexa
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