ArticleThe Journal of biological chemistry2009
Structural model for phenylalkylamine binding to L-type calcium channels.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 52 citations in OpenAlex.
- Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers.Beilstein journal of organic chemistry · 2025Article
- Updates on Intrinsic Medicinal Chemistry of 1,4-dihydropyridines, Perspectives on Synthesis and Pharmacokinetics of Novel 1,4-dihydropyrimidines as Calcium Channel Blockers: Clinical Pharmacology.Current topics in medicinal chemistry · 2025Review
- Modulation of L-type calcium channels in Alzheimer's disease: A potential therapeutic target.Computational and structural biotechnology journal · 2023Review
- P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models.Membranes · 2022Review
- Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies.RSC medicinal chemistry · 2021Review
- Seeking the exclusive binding region of phenylalkylamine derivatives on human T-type calcium channels via homology modeling and molecular dynamics simulation approach.Pharmacology research & perspectives · 2021Article
- A New Computer Model for Evaluating the Selective Binding Affinity of Phenylalkylamines to T-Type CaPharmaceuticals (Basel, Switzerland) · 2021Article
- Phenylalkylamines in calcium channels: computational analysis of experimental structures.Journal of computer-aided molecular design · 2020Article
- Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias.The Journal of innovations in cardiac rhythm management · 2019Review
- Cardiac Rhythm and Molecular Docking Studies of Ion Channel Ligands with Cardiotoxicity in Zebrafish.Cells · 2019Article
- Molecular Determinants of the Differential Modulation of CaMolecular pharmacology · 2018Article
- Article
- In vitro and in silico analysis of the vascular effects of asymmetrical N,N-bis(alkanol)amine aryl esters, novel multidrug resistance-reverting agents.Naunyn-Schmiedeberg's archives of pharmacology · 2016Article
- Functional, electrophysiological and molecular docking analysis of the modulation of Cav 1.2 channels in rat vascular myocytes by murrayafoline A.British journal of pharmacology · 2016Article
- Augmentation of ferulic acid-induced vasorelaxation with aging and its structure importance in thoracic aorta of spontaneously hypertensive rats.Naunyn-Schmiedeberg's archives of pharmacology · 2015Article
- Structural Basis for Pharmacology of Voltage-Gated Sodium and Calcium Channels.Molecular pharmacology · 2015Review
- Ca²⁺ channels and praziquantel: a view from the free world.Parasitology international · 2013Review
- PKC independent inhibition of voltage gated calcium channels by volatile anesthetics in freshly isolated vascular myocytes from the aorta.Cell calcium · 2013Article
- Identification of new batrachotoxin-sensing residues in segment IIIS6 of the sodium channel.The Journal of biological chemistry · 2011Article
- Verapamil block of T-type calcium channels.Molecular pharmacology · 2011Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phenylalkylamines (PAAs), a major class of L-type calcium channel (LTCC) blockers, have two aromatic rings connected by a flexible chain with a nitrile substituent. Structural aspects of ligand-channel interactions remain unclear. We have built a KvAP-based model of LTCC and used Monte Carlo energy minimizations to dock devapamil, verapamil, gallopamil, and other PAAs. The PAA-LTCC models have the following common features: (i) the meta-methoxy group in ring A, which is proximal to the nitrile group, accepts an H-bond from a PAA-sensing Tyr_IIIS6; (ii) the meta-methoxy group in ring B accepts an H-bond from a PAA-sensing Tyr_IVS6; (iii) the ammonium group is stabilized at the focus of P-helices; and (iv) the nitrile group binds to a Ca(2+) ion coordinated by the selectivity filter glutamates in repeats III and IV. The latter feature can explain Ca(2+) potentiation of PAA action and the presence of an electronegative atom at a similar position of potent PAA analogs. Tyr substitution of a Thr in IIIS5 is known to enhance action of devapamil and verapamil. Our models predict that the para-methoxy group in ring A of devapamil and verapamil accepts an H-bond from this engineered Tyr. The model explains structure-activity relationships of PAAs, effects of LTCC mutations on PAA potency, data on PAA access to LTCC, and Ca(2+) potentiation of PAA action. Common and class-specific aspects of action of PAAs, dihydropyridines, and benzothiazepines are discussed in view of the repeat interface concept.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.