Designing Calcium Release Channel Inhibitors with Enhanced Electron Donor Properties: Stabilizing the Closed State of Ryanodine Receptor Type 1
| العنوان: | Designing Calcium Release Channel Inhibitors with Enhanced Electron Donor Properties: Stabilizing the Closed State of Ryanodine Receptor Type 1 |
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| المؤلفون: | Laura J. Owen, Jeffrey D. Singer, Jorge O. Escobedo, Jonathan J. Abramson, Daniel Yaeger, Yanping Ye, Jialu Wang, Robert M. Strongin |
| المصدر: | Molecular Pharmacology. 81:53-62 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Thiazepines, Stereochemistry, Electron donor, Electron Transport, chemistry.chemical_compound, Drug Discovery, Animals, Calcium Signaling, Muscle, Skeletal, Calcium signaling, Pharmacology, RYR1, Voltage-dependent calcium channel, Protein Stability, Chemistry, Ryanodine receptor, Endoplasmic reticulum, Ryanodine Receptor Calcium Release Channel, Articles, Calcium Channel Blockers, musculoskeletal system, Electron transport chain, FKBP, Molecular Medicine, Calcium Channels, Rabbits |
| الوصف: | New drugs with enhanced electron donor properties that target the ryanodine receptor from skeletal muscle sarcoplasmic reticulum (RyR1) are shown to be potent inhibitors of single-channel activity. In this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties. Instead of activating channel activity (~100 μM), the 4-methoxy analog of 4-CmC [4-methoxy-3-methyl phenol (4-MmC)] inhibits channel activity at submicromolar concentrations (IC(50) = 0.34 ± 0.08 μM). Increasing the electron donor characteristics of K201 by synthesizing its dioxole congener results in an approximately 16 times more potent RyR1 inhibitor (IC(50) = 0.24 ± 0.05 μM) compared with K201 (IC(50) = 3.98 ± 0.79 μM). Inhibition is not caused by an increased closed time of the channel but seems to be caused by an open state block of RyR1. These alterations to chemical structure do not influence the ability of these drugs to affect Ca(2+)-dependent ATPase activity of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase type 1. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It seems as if FKBP12, K201, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor characteristics. These results embody strong evidence that designing new drugs to target RyR1 with enhanced electron donor characteristics results in more potent channel inhibitors. This is a novel approach to the design of new, more potent drugs with the aim of functionally modifying RyR1 single-channel activity. |
| تدمد: | 1521-0111 0026-895X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0846f3398d90a76a5497666db82cba4dTest https://doi.org/10.1124/mol.111.074740Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0846f3398d90a76a5497666db82cba4d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210111 0026895X |
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