Permanently Charged Chiral 1,4-Dihydropyridines:  Molecular Probes of L-Type Calcium Channels. Synthesis and Pharmacological Characterization of Methyl (ω-Trimethylalkylammonium) 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridinedicarboxylate Iodide, Calcium Channel Antagonists

Peri, Ravikumar; Padmanabhan, Seetharamaiyer; Rutledge, A.; Singh, Satpal; Triggle, David J.

doi:10.1021/jm000028l

Cited by 107 publications

(35 citation statements)

References 38 publications

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“…These variable length linkers were used to investigate the access pathway and depth of the DHP binding site relatively to the extracellular surface of the cytoplasmic membrane (18,49). (We are not aware of relative potency of the BK-10 enantiomers, but low nanomolar potency was reported for both enantiomers of a related DHP with an octamethylene linker (50).) Docking of (S)-BK-10 in the stern-to-Y 3i10 orientation predicted an energetically optimal binding mode with the linker extending in the interface between domains III and IV along the pore helix of domain III, whereas the trimethylammonium group reached the membrane-exposed entrance to the III/IV domain interface.…”

Section: Resultsmentioning

confidence: 99%

Structural Model for Dihydropyridine Binding to L-type Calcium Channels

Tikhonov

Zhorov

2009

Journal of Biological Chemistry

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1,4-Dihydropyridines (DHPs) constitute a major class of ligands for L-type Ca 2؉ channels (LTCC). The DHPs have a boat-like, six-membered ring with an NH group at the stern, an aromatic moiety at the bow, and substituents at the port and starboard sides. Various DHPs exhibit antagonistic or agonistic activities, which were previously explained as stabilization or destabilization, respectively, of the closed activation gate by the portside substituents. Here we report a novel structural model in which agonist and antagonist activities are determined by different parts of the DHP molecule and have different mechanisms. In our model, which is based on Monte Carlo minimizations of DHP-LTCC complexes, the DHP moieties at the stern, bow, and starboard form H-bonds with side chains of the key DHP-sensing residues Tyr_IIIS6, Tyr_IVS6, and Gln_IIIS5, respectively. We propose that these H-bonds, which are common for agonists and antagonists, stabilize the LTCC conformation with the open activation gate. This explains why both agonists and antagonists increase probability of the long lasting channel openings and why even partial disruption of the contacts eliminates the agonistic action. In our model, the portside approaches the selectivity filter. Hydrophobic portside of antagonists may induce long lasting channel closings by destabilizing Ca 2؉ binding to the selectivity filter glutamates. Agonists have either hydrophilic substituents or a hydrogen atom at their portside, and thus lack this destabilizing effect. The predicted orientation of the DHP core allows accommodation of long substituents in the domain interface or in the inner pore. Our model may be useful for developing novel clinically relevant LTCC blockers. 1,4-Dihydropyridines (DHPs)2 form a major class of L-type Ca 2ϩ channel (LTCC) ligands. DHPs can operate as agonists or antagonists depending on their chemical structure. Importantly, activity of some DHP derivatives may shift from agonism to antagonism (and vice versa) upon site-specific mutation of the channel or modified experimental conditions (for reviews, see Refs. 1 and 2). It has been the dual nature of DHP activity (agonism and antagonism), which has made it challenging for interpretation in structural terms. The other major classes of LTCC ligands, the phenylalkylamines and benzothiazepines, are strictly antagonists.Despite a number of studies, the molecular mechanism for the activity of DHPs on LTCC remains unclear. In the present work we have addressed this problem by combining a molecular modeling approach with analyses of relevant published data. We employed a method of multiple Monte Carlo energy minimizations for docking various DHPs in our earlier reported homology model of LTCC (3), which is based on the crystal structure of the KvAP K ϩ channel (4). We constrained our analyses to potential ligand-binding modes that would be consistent with the features of the ligand-channel activity relationship described in published experiments. These include the structure-activity relationship of the m...

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Section: Resultsmentioning

confidence: 99%

Structural Model for Dihydropyridine Binding to L-type Calcium Channels

Tikhonov

Zhorov

2009

Journal of Biological Chemistry

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“…These 1,4 DHP's have bronchodilator, antiatherosclerotic, antitumor, vasodilator, geroprotective, hapatoprotective, antidiabetic, neuroprotective and platelet anti-aggregator activities [11][12][13] in addition to acting as cerebral antiischemic agents in treatment of Alzeimers disease and as a chemosensitizer in tumor therapy [14][15] . Various cardiovascular drugs such as amlodipine, nifedipine, nicardipine and other related derivatives are dihydropyridyl compounds effective in treatment of hypertension [16][17] . Due to these reasons, 1,4-DHP's have attracted the attention of chemists and hence synthesis of these compounds has been a great focus in organic chemistry.…”

Section: Introductionmentioning

confidence: 99%

An Efficient and Versatile Method for Synthesis of 1,4-Dihydropyridines at Mild Reaction Conditions

Goel¹,

Goel²,

Bajwan³

2018

Chem Sci Trans

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Abstarct: A simple, efficient, versatile and convenient Hantzsch method for synthesis of 1,4-dihydropyridines using ethylacetoacetate, ammonium acetate and substituted arylaldehydes in the presence of tetrabutylammonium hydrogen sulfate (TBAHS) have been reported. Among the popular reported heterogenous solid catalysts, TBAHS has gained high popularity in organic synthesis due to its selectivity, inertness and thermal stability. The method offers advantages such as better yields, short reaction times, a simple work-up procedure, easy isolation of catalyst and reusability of catalyst for several runs.

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“…Another important contribution was a detailed structure activity analysis of a large group of dihydropyridine derivatives that yielded important information about how these compounds interact with L-type calcium channels [3]. The use of permanently charged DHP analogs to probe the depth of the receptor site within the channel/plasma membrane complex was a particularly cleaver approach to delineate some of the key determinants of DHP action on these channels [4][5][6] which was later augmented by mutagenesis studies carried out by others (see below). Finally, the Triggle lab uncovered the reason for tissue selectivity of certain types of DHPs and was able to show that it derived from state dependent inhibition that, for some DHPs, favors block upon membrane depolarization [7].…”

Section: Introductionmentioning

confidence: 99%