1,4-Dihydropyridine calcium channel blockers (1,4-DHPs) are an
important class of drugs which induce relaxation of vascular smooth
muscle, preferentially in arteries and display a negative inotropic
effect on isolated cardiac muscle via binding to a high affinity binding
site in 2-type voltage-dependent [Ca.sup.2+] channel (Poole-Wilson et
al., 2006; 1977; Richard, 2005). In therapy, this class of drugs has
been used in general medical practice worldwide for the treatment of
hypertension and vasospastic angina for over 3 decades (Richard, 2005).
Am. J. Applied Sci., 8 Furthermore, there are considerable evidences
that calcium is an important factor for the induction of epilepsy.
Specifically, different seizure-inducing agents or procedures cause a
rapid intraneuronal influx of calcium ions, which is causally related to
the subsequent epileptiform activity (Richard, 2005; Beig et al., 2009;
Otoom and Hasan, 2006; Samzadeh-Kermani et al., 2009). Conversely,
calcium channel blockers have proven to be effective against the whole
range of convulsive procedures including electro and Pentylenetetrazole
(PTZ) convulsions (Ghasemi et al., 2010; Shafiee et al., 2004) and sound
and high pressure-induced seizures (NGouemo et al., 2010; Luszczki et
al., 2008). Previous quantitative structureactivity relationship studies
of asymmetric derivatives indicated that the vasodilative as well as the
anticonvulsant potency of 1,4-DHPs was dependent upon lipophilic
character of the aliphatic substituents located at 3-, 4- and 5-position
of 1,4-DHPs skeleton (Khoshneviszadeh et al., 2009; Miri et al., 2009).
In light of the previous pharmacological observations (Khoshneviszadeh
et al., 2009; Miri et al., 2009).
In light of the previous pharmacological observations and
therapeutic importance of 1,4-DHP class, it appeared of interest to
design and synthesize new derivatives of mnifedipine in which for the
first time a methyl ester is substituted by 5-phenylcarbamoyl at
5-position of 1,4-DHP ring system. The aim of such aromatic substitution
was undertaken to evaluate the influence of such replacement on calcium
channel blocking activity.
METERIALS AND METHODS
Materials: All reagents were of analytical grades and were used as
received without further purification. Most of the compounds were
obtained from the following companies; Merck, Germany, Sigma-Aldrich,
USA) and all aqueous solutions were prepared with double distilled water
Instruments: NMR spectra were recorded with a Bruker Avance 300 MHz
spectrometer at 300 K, using TMS as an internal standard and
chloroform-d1 as a solvent (Germany). IR spectra (KBr or pure solid)
were measured with a Bruker Tensor 27 spectrometer (Germany). Melting
points were determined with a Buechi B-545 (Romania). MS spectra were
measured with a Finnigan MAT 95 (EI, 70 eV) or with a Finnigan Thermo
Quest TSQ-7000 (ESI) (DCM/MeOH + 10 mmol/L NH4Ac), respectively
(Germany). Elemental analyses were performed by the Analytical
Laboratory of the University of Regensburg. All reactions were carried
out under nitrogen. Chemical structures and names were created using
ChemDraw Ultra 10.0 software.
Synthesis of methylacetoacetic ester a: A stirring solution of
methanol (50 mmol) and 2,2,6-trimethyl-4H-1,3 dixine-4-one (7.1 g, 50
mmol) in 10 mL xylene was refluxed for 30 min. The reaction mixture was
cooled, the xylene was removed and distillation of the mixture afforded
methlacetoacetic ester which was used immediately in subsequent reaction
to synthesize b.
Synthesis of methyl-3-aminocrotonate b: A solution of
methylacetoacetate (4 mmol) and ammonium acetate (6 mmol) in 5 ml
ethanol was refluxed for 24 h. After cooling the mixture, ethanol was
removed and the resulting precipitate, methyl-3-aminocrotonate b is a
white substance, mp 82-83[degrees]C, yield 67%. Then, b was immediately
used in following subsequent reactions.
Synthesis of bezylidene-3-oxo-N-phenylbutanamides c1-c6: A stirring
solution of corresponding substituted benzaldehyde derivative (2 mmol),
correspondong substituted N-phenyl acetoacetamide derivative (2 mmol)
and dry benzene (5 ml) was refluxed for 7 h, during which the resultant
water was removed via Dean-Stark trap. After cooling, the benzene was
removed and the residues were purified on silica-gel with
chloroform-methanol-ethylacetate (92/4/4), to give pure compounds c1-c6.
Synthesis of 5-(phenylcarbamoyl) 2, 6-dimethyl-4-(3-nitro (chloro)
phenyl) 1, 4-dihydropyridine-3-carboxylate derivatives 1-6: A stirring
solution of methyl 3-aminocrotonate b (1.2 mmol) and compounds c1-c6
(1.2 mmol) in 5 ml 2-propanol was refluxed for 24h. After cooling, the
solution was conentrated under reduced pressure and purified by
recrystallization from a suitable solvent to give pure compounds 1-6.
Schematic diagrams 1-3 of the Synthesis
5-(phenylcarbamoyl)2,6-dimethyl-4-(2-nitro(chloro)phenyl)1,4-dihydropyridine-3-carboxylate derivatives (1-6): The synthetic route of the 1,4-DHP
derivatives 1-6 was achieved following four stages outlined in Fig. 1-3.
The first stage and second stage comprised the reaction of methanol with
2, 2, 6-trimethyl-4H-1, 3-dioxin-one to afford methylacetoacetic ester a
(Cheung et al., 2010), which was converted into methy-3-aminocrotonate b
through reaction with ammonium acetate Fig. 1. The third stage was
accomplished by a reaction of corresponding substituted benzaldehydes
with Nphenyl acetoacetamide leading to the corresponding intermediates
c1-c6 Fig. 2 (Cheung et al., 2010). In the fourth stage, titled
compounds 1-6 were synthesized by a modified Hanstzch reaction, using a
procedure reported by Cheung et al. (2010) (53.7-73.3% yield) Fig. 3
(Cheung et al., 2010).
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
Pharmacology investigations on porcine coronary artery:
Method of Isolated tissue bath: Porcine hearts were obtained from
the local slaughterhouse and placed in ice cold oxygenated modified
Krebs-Henseleit Solution (KHS) of the following composition (mM): NaCl
118, KCl 4.7, Ca [Cl.sub.2] 1.6, MgS [O.sub.4] 1.2, K [H.sub.2] P
[O.sub.4] 1.2, NaHC [O.sub.3] 25 and D -glucose 11 (pH 7.4). The left
anterior descending coronary artery (Ramus interventricularis anterior)
and the right coronary artery (A. coronaria dextra) were dissected from
the hearts, cleaned of fat and adhering tissue and cut into rings
(approximately 2-3 mm outer diameter and 3-4 mm in length). Rings were
mounted between two stainless steel hooks, placed in 20-ml
water-jacketed organ chambers and constantly exposed to oxygenated
modified KHS ([O.sub.2] /C [O.sub.2], 95:5%; pH 7.4; 37 [degrees]C).
Tissues were equilibrated for 60 min under a resting tension of 2.0 g
with buffer replacement after 30 min. Isometric force was measured with
FMI TIM-1020 isometric force transducers connected to a TSE 4711
transducer coupler and a Siemens C 1016 compensograph. During a period
of 200 min, tissues were stimulated three times with KCl (30 mM) with 5
and 3-min washing periods between each challenge. The presence or
absence of endothelium was assessed functionally by measuring the extent
of endothelium-dependent relaxation following application of substance P
(10 nM) after the third KCl challenge. To inhibit vascular eicosanoid
production by cyclooxygenase, experiments were performed in the
continuous presence of indomethacin (6 [micro]M) (Moritz et al., 2006).
Compounds: Compounds were dissolved in deionized water (verapamil)
or ethanol (1-6) to a 100 mmol/L stock solution. Stock solutions were
diluted in deionized water with the exception of 1-6 of which 10 mmol/L
solutions were prepared in ethanol. Final organ bath concentrations of
ethanol did not exceed 0.54%. Experiments with vehicle were run in
parallel. Vehicle showed no relaxant response.
Data analysis: Data are presented as a mean [+ or -] S.E.M and the
number of animals used is indicated by n. Antagonist potencies were
expressed as [pEC.sub.50] values (negative logarithm to base 10 of the
molar concentration of the agonist producing 50% of the maximum
response). Maximal responses were expressed as [E.sub.max] values
(percentage of the maximum contractile response to KCl). Multiple
comparisons between treatment groups were performed using the analysis
of variance (ANOVA) followed by a Tukey's test. All other
statistical evaluations were carried out using Student's t-test
(unpaired for comparison of means between independent experiments,
paired for comparison of means between experiment and control) after
checking the homogeneity of the variances by F-test. P values Less than
0.05 were considered to be significant.
Identifacation and charterization of synthesized compounds: The
following are the properties and charterization of synthesized
Yield: 53%, m.p.: 115-116 [degrees]C; Anal. Calcd. For [C.sub.17]
[H.sub.13] [N.sub.2] [O.sub.4] Br: C, 52.46; H, 3.37; N, 7.20. Found: C,
52.05; H, 3.43; N, 7.48.
Yield: 55%, m.p.: 119-120 [degrees]C; Anal. Calcd. For [C.sub.17]
[H.sub.13] [N.sub.2] [O.sub.4] Cl: C, 53.92; H, 3.46; N, 3.70. Found: C,
53.51; H, 3.67; N, 3.28.
c3: Yield: 47%, m.p.: 113-114 [degrees]C;
Anal. Calcd. For [C.sub.17] [H.sub.12] N [O.sub.4] [CL.sub.3]: C,
55.39; H, 3.24; N, 3.80. Found: C, 54.91; H, 3.28; N, 3.49.
c4: Yield: 49%, m.p.: 118-119 [degrees]C; Anal. Calcd. [C.sub.19]
[H.sub.18] N [O.sub.2] Cl: C, 69.62; H, 5.53; N, 4.27. Found: C, 69.23;
H, 5.57; N, 3.99.
c5: Yield: 54%, m.p.: 110-111 [degrees]C;
Anal. Calcd. For [C.sub.19] [H.sub.18] [N.sub.2] [O.sub.4]: C,
67.44; H, 5.36; N, 8.28. Found: C, 67.75; H, 5.58; N, 8.
c6: Yield: 56%, m.p.: 121 - 122 [degrees]C;
Anal. Calcd. For [C.sub.17] [H.sub.12] [N.sub.2] [O.sub.4]
[CL.sub.2]: C, 53.85; H, 3.19; N, 7.39. Found: C, 53.84; H, 4.03; N,
Methyl 5-(4-bromophenylcarbamoyl)-2,6-dimethyl-4(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate 1: IR (KBr): [nu]([cm.sup.-1]) 3348 (NH
pyridine), 1700 (C=O ester), 1680 (C=O amide); [.sup.1] H NMR (CD
[CL.sub.3]): [delta] = 8.18 (t, J= 1.90 Hz, 1H), 8.11-8.06 (m, 1H),
7.74-7.67 (m, 1H), 7.48 (t, J= 7.80, 1H), 7.40-7.34 (m, 2H), 7.27-7.20
(m, 2H), 7.04 (bs, 1H, amide), 5.74 (bs, 1H), 5.01 (s, 1H, [H.sub.4]),
3.68 (s, 3H, OC[H.sub.3]), 2.35 (s, 3H, C[H.sub.3]), 2.34 (s, 3H,
C[H.sub.3]); MS: m/z (%) 486 ([M.sup.+], 44), 456 (100), 425 (22), 299
(10); Anal. Calcd. For [C.sub.22] [H.sub.20] Br [H.sub.3] [O.sub.5]: C,
54.33; H, 4.15; N, 8.64. Found: C, 53.84; H, 4.03; N, 8.58.
Methyl 5-(4-bromophenylcarbamoyl)-4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate 2: IR (KBr): [nu]([cm.sup.-1]) 3312 (NH
pyridine), 1679 (C=O ester), 1614 (C=O amide); [.sup.1] H NMR (CDCl3):
[delta] = 7.38-7.16 (m, 8H, aromatic), 7.04 (bs, 1H, amide), 5.68 (bs,
1H), 4.81 (s, 1H, [H.sub.4]), 4.78 (s, 1H, [H.sub.4]), 3.68 (s, 3H, OC
[H.sub.3]), 2.35 (s, 3H, C [H.sub.3]), 2.34 (s, 3H, C [H.sub.3]); MS:
m/z (%) 475 ([M.sup.+], 97), 472 (17), 397 (15); Anal. Calcd. For
[C.sub.22] [H.sub.20] BrCl [N.sub.2] [O.sub.3] 0.25 [H.sub.2] O: C,
55.17; H, 4.28; N, 5.85. Found: C, 55.03; H, 4.73; N, 5.50.
dimethyl-1,4-dihydropyridine-3-carboxylate 3: IR (KBr):
[nu]([cm.sup.-1]) 3250 (NH pyridine), 1660 (C=O ester), 1608 (C=O
amide); [.sup.1] H NMR (CDCl3): [delta] = 7.41-7.16 (m, 7H, aromatic),
6.88 (bs, 1H, amide), 5.68 (bs, 1H), 5.01 (s, 1H, [H.sub.4]), 3.07 (s,
3H, OC [H.sub.3]), 2.41 (s, 3H, C [H.sub.3]), 2.36 (s, 3H, C [H.sub.3]);
MS: m/z (%) 465 ([M.sup.+], 100), 431 (12); Anal. Calcd. For [C.sub.22]
[H.sub.19] [CL.sub.3] [N.sub.2] [O.sub.3]: C, 56.73; H, 4.11; N, 6.01.
Found: C, 56.74; H, 4.12; N, 5.91.
Methyl 4-(3-chlorophenyl)-5-(2,6-dimethylphenylcarbamoyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate 4: IR (KBr): [nu]([cm.sup.-1])
3267 (NH pyridine), 1684 (C=O ester), 1645 (C=O amide); [.sup.1] H NMR
(CD [CL.sub.3]): [delta] = 7.39-7.01 (m, 7H, aromatic), 6.51 (bs, 1H,
amide), 5.69 (bs, 1H), 4.91 (s, 1H, [H.sub.4]), 3.68 (s, 3H, OC
[H.sub.3]), 2.39 (s, 3H, C [H.sub.3] pyridine), 2.37 (s, 3H, C [H.sub.3]
pyridine), 1.93 (s, 3H, C [H.sub.3] phenylcarbamoyl), 1.59 (s, 3H, C
[H.sub.3] phenylcarbamoyl); MS: m/z (%) 425 ([M.sup.+], 100), 423 (6);
Anal. Calcd. For [C.sub.24] [H.sub.25] Cl [N.sub.2] [O.sub.3]: C, 67.84;
H, 5.93; N, 6.59. Found: C, 67.95; H, 6.21; N, 6.31.
Methyl 5-(2,6-dimethylphenylcarbamoyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate 5: IR (KBr): [nu](cm-1) 3272 (NH
pyridine), 1685 (C=O ester), 1606 (C=O amide); [.sup.1] H NMR (CDCl3):
[delta] ppm = 8.24 (t, J = 1.92 Hz, 1H), 8.11-8.05 (m, 1H), 7.81 -7.70
(d, J = 9.68 Hz, 1H), 7.46 (t, J = 7.96 Hz, 1H), 7.11-6.97 (m, 3H), 6.54
(bs, 1H, amide), 5.75 (bs, 1H), 5.12 (s, 1H, H4), 3.69 (s, 3H, OC
[H.sub.3]), 2.39 (s, 3H, C [H.sub.3] pyridine), 2.34 (s, 3H, C [H.sub.3]
pyridine), 1.93 (s, 3H, C [H.sub.3] phenylcarbamoyl), 1.59 (s, 3H, C
[H.sub.3] phenylcarbamoyl); MS: m/z (100%) 34 ([M.sup.-], 100), 311
(46); Anal. Calcd. For [C.sub.24] [H.sub.25] [N.sub.3] [O.sub.5]: C,
66.19; H, 5.79; N, 9.65. Found: C, 66.18; H, 6.13; N, 9.20.
Methyl 5-(2,6-dichlorophenylcarbamoyl)-2,6-dimethyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3-carboxylate 6: IR (KBr): [nu]([cm.sup.-1])
3261 (NH pyridine), 1696 (C=O ester), 1610 (C=O amide); [.sup.1] H NMR
(CDCl3): [delta]= ppm 8.23 (t, J = 1.92 Hz, 1H), 8.10-8.05 (m, 1H),
7.78-7.72 (m, 1H), 7.50-7.42 (m, 1H), 7.31-7.25 (m, 3H), 6.79 (bs, 1H,
amide), 5.79 (bs, 1H), 5.14 (s, 1H, [H.sub.4]), 3.69 (s, 3H, OC
[H.sub.3]), 2.39 (s, 3H, C [H.sub.3]), 2.35 (s, 3H, C [H.sub.3]); MS:
m/z (%) 474 ([M.sup.-], 100), 350 (8); Anal. Calcd. For [C.sub.22]
[H.sub.19] [CL.sub.2] [N.sub.2] [O.sub.5]: C, 55.48; H, 4.02; N, 8.82.
Found: C, 55.44; H, 4.21; N, 8.70.
Pharmacological activity: The calcium channel blocking (CCBA) of 1,
4-DHP derivatives 1-6 was determined using PCASM assay (Moritz et al.,
2006). The CCBA results of tested compounds are shown in Table 2.
Properties of synthesized compound: The prepared compounds are
white or light yellow crystalline solids, soluble at room temperature in
acetone and chloroform, by heating in lower alcohols, benzene, toluene
and xylene and insoluble in water. The structure, molecular formulae,
molecular weights, melting points and yields of the new
5-phenylcarbamoly derivatives are presented in Table 1, the results
shows that the molecular weight of the prepared compounds were ranged
between 424.91 - 476.30, the melting points between 108-251 [degrees]C
and a good yield of synthesized compounds was obtained which ranges
[TABLE 1 OMITTED]
Pharmacological activity: Whereas compounds 1-2 failed to show any
blocking activity in the PCASM assay, the compounds 3-6 were found to be
active in different degrees in Table 2. The results observed indicated
that both compounds 5 and 6 were the most active, as compound 5 and 6
showed a calcium channel blocking potency of 6.46 [+ or -] 0.07 and 6.35
[+ or -] 0.10 respectively. The observed antagonistic results for 5 and
6 are comparable with the standard calcium channel blocker verapamil
which exhibited a blocking potency of 6.97 [+ or -] 0.15 and the potency
of m-nifedipine (7.48 [+ or -] 0.05) (Moritz et al., 2006) was not
achieved. On the other hand, the maximal antagonistic effect, expressed
as a percentage [E.sub.max] value, of 106 [+ or -] 5 observed by
verapamil and of 101 [+ or -] 1 by m-nifedipine was not achieved by all
derivatives, since the highest [E.sub.max] results was found by 99 [+ or
-] 1, observed for both compounds 3 and 5. The obtained results indicate
that the calcium channel blocking activity of m-nifedipine maintains,
even by substituting an ester moiety with an aromatic substituted amide
moiety at C5-position. Furthermore, structure-activity relationships
observed in the present study underline the important impact of the
presence of 2, 6-dimethyl-or 2, 6-dichloro-substituents at phenyl ring
of 5-phenylcarbamoyl moiety, since absence of both substituents or
shifting of one substituent into 4-position led to completely inactive
compounds. The calcium channel blocking activity results for the
compounds 1 and 2 supported this hypothesis, where presence of brom at
4-position led to derivatives which failed to exhibit any blocking
activity at porcine coronary artery smooth muscles, even with presence
of a 3'-chloro (or 3' -nitro)phenyl substitute on 1,4-DHP
ring. Moreover, it has been observed that a 3'-position of nitro-or
chlor group necessitates the presence of a 2, 6-dimethyl-or 2,
6-dichloro substituents on the 5-phenyl carbamoyl moiety.
The combination of such substitutes was realized in compound 5 and
6 which were found to exhibit the highest calcium channel blocking
potency (6.46 [+ or -] 0.07) and (6.35 [+ or -] 0.10), respectively.
Since compounds 4-6 were moderate to high potent in relaxing
porcine coronary arteries, a cumulative concentration-response curves to
both compounds was established to further investigate whether a
competitive antagonism is present or not. The antagonist potencies and
maximal responses are summarized in Table 2. The effects were not
different in tissues with endothelium compared to those without
endothelium. The most potent vasodilator was compound 5 which showed a
vasodilator effect similar to that of verapamil, the standard antagonist
of test model used in the present study (Fig. 4 and 5).
[FIGURE 4 OMITTED]
[FIGURE 5 OMITTED]
Vasodilator effects to compounds 4-6 were not inhibited by the
estrogen receptor antagonist ICI 182,780 (10 [micro] M), neither in
endothelium-intact nor in endothelium-denuded arterial rings (not
shown), indicating that relaxation effects were observed only through a
competitive antagonistic interaction of tested compounds with calcium
channels of porcine coronary artery smooth muscles.
The obtained results reveal that a modification of an ester moiety
in m-nifedipine through a replacement with an aromatic substituted amide
led to a new class of 5-phenylcarbamoyl derivatives of 1, 4-DHPs with
calcium channel blocking activity in porcine coronary arteries. Although
some of the developed compounds possess maximal effects comparable to
m-nifedipine. Since amides are known to be more resistant to
metabolizing enzymes than their corresponding esters, the developed
compounds in the present study will predicatively show an increased
metabolic stability and consequently longer duration of actions compared
to m-nifedipine and could be, therefore, suitable candidates for further
optimization to be evaluated as a new class of antihypertensive drugs.
On the other hand and due to their expected higher lipophilic
character, continuous research efforts are required to investigate their
cardiovascular profile. Furthermore, additional modifications of the
titled compounds are needed to allow pharmacological investigations of
their effects in the central nervous system, e.g., cognitive disorders,
as there are considerable evidences that calcium is an important factor
for the induction of epilepsy and calcium channel blockers, especially
of 1,4-DHP with high lipophilic character, proved to be effective
against the whole range of convulsive procedures including electro and
Pentylenetetrazole (PTZ) convulsions (Ghasemi et al., 2010; Shafiee et
al., 2004). The latter pharmacological investigations are required to
prove the potential of titled compounds as an adjuvant, non-sedative
antiepileptic drugs, especially in those patients in whom conventional
therapy has been inadequate or in patients who are refractory to
anticonvulsant treatment, or in cases of untreatable epilepsy.
The researchers are thankful to Professor Heinz H. Pertz, Institute
of Biology at Free University of Berlin, Germany for his kind help in
the pharmacological testing of titled compounds.
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Corresponding Author: Bassem Sadek, Department of Pharmaceutical
Sciences, College of Pharmacy, Al-Ain University of Science and
Technology, P.O. Box 64141, Al Ain, United Arab Emirates Tel.:
+97137611185 Fax: +97137611198
(1) Bassem Sadek, (1) Khairi Mustafa Salem Fahelelbom, (2)
Laurentiu Morusciag and (3) Sigurd Elz
(1) Department of Pharmaceutical Sciences, College of Pharmacy,
Al-Ain University of Science and Technology, P.O. Box 64141, Al Ain,
United Arab Emirates
(2) Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Carol Davila" University of Medicine and Pharmacy, Traian Vuia 6,
Sect. 2, 020956, Bucharest, Romania
(3) Department of Pharmaceutical/Medicinal Chemistry, Faculty of
Chemistry and Pharmacy, University of Regensburg, University Str. 31,
D-93053 Regensburg, Germany
Table 2: Observed calcium channel blocking activities for compounds 1-6
sub.50] .max] (%)
[+ or -] [+ or -] n
No. [R.sub.1] [R.sub.2] SEM SEM
1 [NO.sub.2] 4-bromophenyl no effect - 3
2 Cl 4-bromophenyl no effect - 4
3 Cl 2, 6-dichlorophenyl 4.37[+ or 99[+ or -]1 5
4 Cl 2, 6-dimethylphenyl 5.37[+ or 92[+ or -]7 3
5 [NO.sub.2] 2, 6-dimethylphenyl 6.46[+ or 99[+ or -]1 5
6 [NO.sub.2] 2, 6-dichlorophenyl 6.35[+ or 92[+ or -]7 4
Verapamil - - 6.97[+ or 106[+ or -]5 5
Nifedipine 7.48[+ or 101[+ or -
-]0.05 * -]1 *
* (Moritz et al., 2006)