1,4-Dihydropyridine Calcium Channel Blockers: Homology Modeling of the Receptor and Assessment of Structure Activity Relationship

Shaldam, Moataz A.; El-Hamamsy, Mervat H.; Esmat, Eman Ahmed; El‐Moselhy, Tarek F.

doi:10.1155/2014/203518

Cited by 18 publications

(22 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Voltage-gated calcium channels play an important role in the entry of Ca 2+ ions into excitable cells and are also involved in a series of calcium-dependent processes, such as muscle contraction, hormone or neurotransmitter release, gene expression, and cell death (Augustine et al 1987;Miller 1987). Voltage-gated calcium channels are blocked by 1,4-d i h y d r o p y r i d i n e s ( D H P s ) s u c h a s n i f e d i p i n e , phenylalkylamines such as verapamil, and benzothiazepines such as diltiazem (Shaldam et al 2014). They are multisubunit complexes, comprising alpha-1, alpha-2, beta, and delta subunits.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of a calcium channel blocker “diltiazem” on aluminum chloride-induced dementia in mice

Rani

Neha

Sodhi

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

Many studies report that heavy metals such as aluminum are involved in amyloid beta aggregation and neurotoxicity. Further, high concentration of aluminum in the brain deregulates calcium signaling which contributes to synaptic dysfunction and halts neuronal communication which ultimately leads to the development of Alzheimer's disease. Recently, diltiazem, a calcium channel blocker clinically used in angina, is reported to decrease amyloid beta production by inhibiting calcium influx, decreasing inflammation and oxidative stress. However, the probable role of this drug in aluminum chloride (AlCl3)-induced experimental dementia is yet to be explored. Therefore, the present study is designed to investigate the effect of AlCl3-induced dementia in mice. Morris water maze test and elevated plus maze were utilized to evaluate learning and memory. Various biochemical estimations including brain acetylcholinesterase activity (AChE), brain total protein, thiobarbituric acid-reactive species (TBARS) level, reduced glutathione (GSH) level, nitrate/nitrite, and superoxide dismutase (SOD) were measured. AlCl3 significantly impaired learning and memory and increased brain AChE, brain total protein, TBARS, and nitrate/nitrite and decreased brain GSH or SOD. On the other hand, treatment with diltiazem significantly reversed AlCl3-induced behavioral and biochemical deficits. The present study indicates the beneficial role of diltiazem in AlCl3-induced dementia.

show abstract

Section: Discussionmentioning

confidence: 99%

Protective effect of a calcium channel blocker “diltiazem” on aluminum chloride-induced dementia in mice

Rani

Neha

Sodhi

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

show abstract

“…Atoms N1 and C4 of the 1,4-DHP ring can be marginally displaced from the mean plane of the boat (Linden et al, 2002). An aryl group in the 4-position of the 1,4-DHP ring is essential for optimal activity (Shaldam et al, 2014). One study showed that an aryl ring with halogen or other electron-withdrawing groups exhibits higher receptorbinding activity (Takahashi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The effect of bromine scanning around the phenyl group of 4-phenylquinolone derivatives

Steiger

Monacelli

et al. 2014

Acta Crystallogr C

View full text Add to dashboard Cite

Three quinolone compounds were synthesized and crystallized in an effort to study the structure-activity relationship of these calcium-channel antagonists. In all three quinolones, viz. ethyl 4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (I), ethyl 4-(3-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (II), and ethyl 4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, (III), all C21H24BrNO3, common structural features such as a flat boat conformation of the 1,4-dihydropyridine (1,4-DHP) ring, an envelope conformation of the fused cyclohexanone ring and a bromophenyl ring at the pseudo-axial position and orthogonal to the 1,4-DHP ring are retained. However, due to the different packing interactions in each compound, halogen bonds are observed in (I) and (III). Compound (III) crystallizes with two molecules in the asymmetric unit. All of the prepared derivatives satisfy the basic structural requirements to possess moderate activity as calcium-channel antagonists.

show abstract

“…This again implies the importance of the ring lipophilicity in the calcium antagonist activity of DHPs. 33) Ester groups at 3-and 5-positions are simply methyl ester groups in both nifedipine and the two compounds 3a and g. The down methyl ester group stabilizes the lipophilic bracelet while the other methyl ester group is projected in the water lake core of the receptor and participates in chelating the Ca 2+ cofactor (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

“…This compound has benzyl ester substituent with total ten carbon atom side chain (five extended carbon atom at 3-and 5-positions). This bulky side chain may interfere with the affinity axis (Tyr 1149 and Tyr 1460 ) binding 33) which may result in abolishing ring to ring hydrophobic attraction force between the chlorophenyl ring and Tyr 1460 . The down benzyl ester group phenyl ring makes the affinity axis instead of important stabilization of the hydrophobic bracelet.…”

Section: Resultsmentioning

confidence: 99%

“…This is a demanding to bias the formation of H-bond with Tyr 1149 -an important DHP sensing residue-while takes the orientation described by SAR. 33) Docking template consisted of one hydrogen bond donor, two rings, three hydrogen bond acceptors and five steric moieties. Iterative simplex algorithm was chosen to perform docking process with 15 runs per ligand, 50 population size, 100 max iteration and 8 poses for each ligand.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis, Evaluation of Pharmacological Activity, and Molecular Docking of 1,4-Dihydropyridines as Calcium Antagonists

Shaldam

El-Hamamsy

Saleh

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

1,4-Dihydropyridine (DHP) is an important class of calcium antagonist. It inhibits the influx of extracellular Ca2 through L-type voltage-dependent calcium channels. Two series of nifedipine analogues were synthesized and evaluated as calcium antagonists. The ortho-nitrophenyl ring of nifedipine was replaced with an ortho-or a meta-chlorophenyl substituent. The IC 50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution with groups of suitable bulkiness, such as ethyl ester, at the 3-and 5-positions of the DHP ring gave 3h, which is approximately three-fold more active than nifedipine as a calcium antagonist. A docking study with the DHP receptor model was performed to interpret the differences in calcium antagonist activities. The molecular docking study demonstrated that the lipophilicity of the substituted phenyl group at the 4-position of the DHP ring is an important factor that could increase the activity of the calcium antagonist taking the steric factor into consideration. Bulky groups interfere with ring-to-ring hydrophobic interaction with Tyr 1460 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3-and 5-positions of the DHP ring as an approach to increase activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring may ensure strong binding to the receptor and hence stabilization of the closed-channel conformation.Key words 1,4-dihydropyridine (DHP); calcium channel blocker; pharmacological evaluation; synthesis; molecular docking Calcium is essential in all living organisms. Different types of calcium channels can control the influx of calcium ions into cells.1) The influx of calcium ion into the cell takes place in both normal functioning and in pathologic processes.2,3) This raises the importance of calcium channels as targets for many drugs. Various drugs can modulate either agonist or antagonist, the calcium ion entry through L-type Ca 2+ channels. 4-7)Calcium antagonists have a various pharmacological activity including antihypertensive and antianginal agent, [8][9][10] Several studies that targeted structure-activity relationship (SAR) of DHP action at the L-type channel have focused on the importance of the lipophilicity of DHPs in increasing calcium antagonist activity. [21][22][23][24] Chlorophenyl ring is a lipophilic group that can be introduced in 4-position of the DHP ring and hence increases the lipophilicity of the target compounds. In this research, ortho-and meta-chlorophenyl rings in 4-position of the DHP ring was used. Also side chain esters in 3-and 5-positions were designed to increase lipophilicity to investigate lipophilic effect on calcium antagonist activity. Results and DiscussionChemistry Two series of DHP derivatives were synthesized. A series of symmetric achiral DHPs (3a-k) has been synthesized by using classical Hantzsch condensation 25) as shown in Chart 1. The asymmetric chiral DHPs series (6a-n) has been synthesized by a modified Hantz...

show abstract

1,4-Dihydropyridine Calcium Channel Blockers: Homology Modeling of the Receptor and Assessment of Structure Activity Relationship

Cited by 18 publications

References 64 publications

Protective effect of a calcium channel blocker “diltiazem” on aluminum chloride-induced dementia in mice

Protective effect of a calcium channel blocker “diltiazem” on aluminum chloride-induced dementia in mice

The effect of bromine scanning around the phenyl group of 4-phenylquinolone derivatives

Synthesis, Evaluation of Pharmacological Activity, and Molecular Docking of 1,4-Dihydropyridines as Calcium Antagonists

Contact Info

Product

Resources

About