1-[5-Arylfurfurylidene)amino]hydantoins. A New Class of Muscle Relaxants

Snyder, H. R.; Davis, Charles S.; Bickerton, Robert K.; Halliday, Robert P.

doi:10.1021/jm00317a011

Cited by 172 publications

(60 citation statements)

References 2 publications

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“…Physiologically active analogues of dantrolene also inhibited skeletal muscle SR vesicle [ 3 H]ryanodine binding (Fig. 3), and the relative potency of the different analogues reflected their potency in inhibiting skeletal muscle contractility (31)(32)(33). In addition, dantrolene inhibition of skeletal muscle SR vesicle 45 Ca 2ϩ release (Fig.…”

Section: Dantrolene Inhibition Of Skeletal Muscle Ryrs Is Consistent mentioning

confidence: 90%

Dantrolene Inhibition of Sarcoplasmic Reticulum Ca2+Release by Direct and Specific Action at Skeletal Muscle Ryanodine Receptors

Fruen

Mickelson

Louis

1997

Journal of Biological Chemistry

196

169

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The skeletal muscle relaxant dantrolene inhibits the release of Ca 2؉ from the sarcoplasmic reticulum during excitation-contraction coupling and suppresses the uncontrolled Ca 2؉ release that underlies the skeletal muscle pharmacogenetic disorder malignant hyperthermia; however, the molecular mechanism by which dantrolene selectively affects skeletal muscle Ca 2؉ regulation remains to be defined. Here we provide evidence of a high-affinity, monophasic inhibition by dantrolene of ryanodine receptor Ca 2؉ channel function in isolated sarcoplasmic reticulum vesicles prepared from malignant hyperthermia-susceptible and normal pig skeletal muscle. In media simulating resting myoplasm, dantrolene increased the half-time for 45 Ca 2؉ release from both malignant hyperthermia and normal vesicles approximately 3. The muscle relaxant dantrolene is a potent and specific inhibitor of skeletal muscle excitation-contraction (E-C) 1 coupling (1). Dantrolene (ϳ10 M) reduces skeletal muscle twitch force by approximately 75% (2) and shifts the sensitivity of contractile activation to higher voltages (3, 4), these effects being attributed to a partial block by dantrolene of Ca 2ϩ release from the sarcoplasmic reticulum (SR) (1,5,6). In contrast to these pronounced effects on skeletal muscle, effects of dantrolene on cardiac muscle contractility are mild or absent (1, 5, 7). Clinically, dantrolene has proven effective in the treatment of malignant hyperthermia (MH), a potentially fatal genetic disorder of skeletal muscle E-C coupling in which exposure to volatile anesthetics triggers uncontrolled SR Ca 2ϩ release, muscle contracture, and accelerated metabolism (8).The molecular basis of the action of dantrolene remains undefined but is generally presumed to involve either direct or indirect inhibitory effects on ryanodine receptor (RYR) Ca 2ϩ channels. To date, three RYR isoforms have been identified in mammalian tissues and are termed RYR1, RYR2, and RYR3 (9). In skeletal muscle, the RYR1 isoform is the major pathway for SR Ca 2ϩ release during E-C coupling, and defects in these channels have been linked to MH susceptibility in pigs and in certain human families (8, 10). Moreover, recent evidence indicates that high-affinity [3 H]dantrolene and [ 3 H]ryanodine binding sites are localized to the same or closely associated skeletal muscle SR membrane fractions (11, 12). RYR1 channels thus constitute a likely target for the physiologic and therapeutic actions of dantrolene on skeletal muscle Ca 2ϩ regulation. Nonetheless, the precise mechanism by which dantrolene may affect the activation of RYR1 channels has remained unclear. In particular, it is not yet clear how dantrolene may alter RYR1 activation by the physiologic effectors of these channels that have been identified in studies using isolated SR vesicles preparations (13). In addition, whether the effects of dantrolene may reflect a direct interaction with the RYR1 channel complex itself or rather require dantrolene binding to a separate and as yet unidentified regulatory molecu...

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Section: Dantrolene Inhibition Of Skeletal Muscle Ryrs Is Consistent mentioning

confidence: 90%

Dantrolene Inhibition of Sarcoplasmic Reticulum Ca2+Release by Direct and Specific Action at Skeletal Muscle Ryanodine Receptors

Fruen

Mickelson

Louis

1997

Journal of Biological Chemistry

196

169

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“…For the synthesis of 2-arylfurans different methods are required. The muscle relaxant dantrolene (3), commonly used for the treatment of life-threatening complications during anaesthesia, [3] for instance, has been synthesized from furfural and an arenediazonium salt [4] through a Cu-catalysed Meerwein arylation. [5] Formation of the quinazoline-furan C-C bond in the anticancer agent lapatinib (4), a tyrosine kinase inhibitor, was achieved through a Suzuki-Miyaura coupling between a 2-furylboronic acid and an appropriately substituted quinazolinyl iodide ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Ru‐ and Pd‐Catalysed Synthesis of 2‐Arylfurans by One‐Flask Heck Arylation/Oxidation

Schmidt¹,

Geißler²

2011

Eur J Org Chem

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Abstract2,5‐Disubstituted furans were synthesized by one‐flask Heck arylation/oxidation sequences. The starting materials are 2‐substituted 2,3‐dihydrofurans, conveniently available by RCM/isomerization sequences, and arenediazonium salts. These react in ligand‐free Heck reactions to afford 2,5‐disubstituted 2,5‐dihydrofurans, which are oxidized to the corresponding furans without isolation or intermediate workup. The oxidation is conveniently achieved with chloranil or DDQ, depending on the substrate.

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“…Dantrolene sodium is a hydrantoin derivative that was initially described as a muscle relaxant [25] , but later found to be a potent therapeutic agent for patients suffering from the rare life-threatening condition known as malignant hyperthermia (MH) [26] . Patients susceptible to MH typically have inherited mutations in the type 1 ryanodine receptor (RyR1) primarily found in skeletal muscle [27] .…”

Section: Dantrolenementioning

confidence: 99%

Targeting ryanodine receptors for anti-arrhythmic therapy

McCauley

Wehrens

2011

Acta Pharmacol Sin

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Antiarrhythmic drugs are a group of pharmaceuticals that suppress or prevent abnormal heart rhythms, which are often associated with substantial morbidity and mortality. Current antiarrhythmic drugs that typically target plasma membrane ion channels have limited clinical success and in some cases have been described as being pro-arrhythmic. However, recent studies suggest that pathological release of calcium (Ca 2+ ) from the sarcoplasmic reticulum via cardiac ryanodine receptors (RyR2) could represent a promising target for antiarrhythmic therapy. Diastolic SR Ca 2+ release has been linked to arrhythmogenesis in both the inherited arrhythmia syndrome 'catecholaminergic polymorphic ventricular tachycardia' and acquired forms of heart disease (eg, atrial fi brillation, heart failure). Several classes of pharmaceuticals have been shown to reduce abnormal RyR2 activity and may confer protection against triggered arrhythmias through reduction of SR Ca 2+ leak. In this review, we will evaluate the current pharmacological methods for stabilizing RyR2 and suggest treatment modalities based on current evidence of molecular mechanisms.

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1-[5-Arylfurfurylidene)amino]hydantoins. A New Class of Muscle Relaxants

Cited by 172 publications

References 2 publications

Dantrolene Inhibition of Sarcoplasmic Reticulum Ca2+Release by Direct and Specific Action at Skeletal Muscle Ryanodine Receptors

Dantrolene Inhibition of Sarcoplasmic Reticulum Ca2+Release by Direct and Specific Action at Skeletal Muscle Ryanodine Receptors

Ru‐ and Pd‐Catalysed Synthesis of 2‐Arylfurans by One‐Flask Heck Arylation/Oxidation

Targeting ryanodine receptors for anti-arrhythmic therapy

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