The separation of antagonist from agonist effects of trisubstituted purines on CaV2.2 (N‐type) channels

Buraei, Zafir; Elmslie, Keith S.

doi:10.1111/j.1471-4159.2008.05248.x

Cited by 18 publications

(43 citation statements)

References 52 publications

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“…The agonist effect results from (R)-roscovitine specifically binding to activated Ca V 2 channels to slow channel closing (14,15), which results in a significant enhancement of action potential induced calcium influx (14). The antagonist effect appears to result from (R)-roscovitine preferentially enhancing occupancy of a "resting" inactivated state to inhibit channel activity (18). Interestingly, the racemic variant (S)-roscovitine has been found to exhibit only an antagonist effect on N-channels, which is one result supporting unique binding sites for the agonist versus antagonist effects (14,15,18).…”

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confidence: 75%

“…We further investigated this idea by examining the effect of (S)-roscovitine on L-type channels, which was useful in differentiating multiple roscovitine binding sites on N-type channels (15,17,18). Using 25-ms voltage steps to ϩ20 mV, we verified that 100 M (R)-roscovitine slowed L-channel activation (15,19) (Fig.…”

Section: (S)-roscovitine Does Not Affect L-channel Activation-wementioning

confidence: 99%

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“…The antagonist effect appears to result from (R)-roscovitine preferentially enhancing occupancy of a "resting" inactivated state to inhibit channel activity (18). Interestingly, the racemic variant (S)-roscovitine has been found to exhibit only an antagonist effect on N-channels, which is one result supporting unique binding sites for the agonist versus antagonist effects (14,15,18).L-type channels are also inhibited by (R)-roscovitine, but by a unique mechanism relative to N-channels (19). L-channel inhibition results from slowed activation and enhanced open state voltage-dependent inactivation (VDI), 3 but the resting inactivated state is not affected.…”

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Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation

Yarotskyy

Gao

et al. 2010

Journal of Biological Chemistry

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L-type (Ca V 1.2) calcium channel antagonists play an important role in the treatment of cardiovascular disease. (R)-Roscovitine, a trisubstituted purine, has been shown to inhibit L-currents by slowing activation and enhancing inactivation. This study utilized molecular and pharmacological approaches to determine whether these effects result from (R)-roscovitine binding to a single site. Using the S enantiomer, we find that (S)-roscovitine enhances inactivation without affecting activation, which suggests multiple sites. This was further supported in studies using chimeric channels comprised of N-and L-channel domains. Those chimeras containing L-channel domains I and IV showed (R)-roscovitine-induced slowed activation like that of wild type L-channels, whereas chimeric channels containing L-channel domain I responded to (R)-roscovitine with enhanced inactivation. We conclude that (R)-roscovitine binds to distinct sites on L-type channels to slow activation and enhance inactivation. These sites appear to be unique from other calcium channel antagonist sites that reside within domains III and IV and are thus novel sites that could be exploited for future drug development. Trisubstituted purines could become a new class of drugs for the treatment of diseases related to hyperfunction of L-type channels, such as Torsades de Pointes.Cardiac L-type (Ca V 1.2) channels are central to the regulation of a number of physiological processes (1, 2). Activation of these channels in cardiac and smooth muscle generates the calcium influx that triggers calcium release from the sarcoplasmic reticulum (3) to induce contraction. In contrast, inactivation of these channels provides a negative feedback mechanism to limit calcium influx into the cardiac myocyte, which helps protect from excessive calcium influx that can lead to cardiac arrhythmias (3). L-channel antagonists are routinely used to treat cardiovascular diseases, such as hypertension and angina pectoris (4 -8). Therefore, drugs that inhibit L-channel function have high clinical relevance.Roscovitine is a 2,6,9-trisubstituted purine that was originally developed as a selective blocker of cyclin-dependent kinases (9) and is currently undergoing phase II clinical trials as an anticancer drug (10). It has recently become apparent that roscovitine can affect voltage-dependent ion channels at clinically relevant concentrations (10 -50 M) (10 -13). We (14, 15) and others (16,17) have shown that (R)-roscovitine differentially affects voltage-dependent calcium channels. (R)-Roscovitine has two effects on Ca V 2 channels (N-type, P/Q-type, and R-type), which are a rapid onset agonist effect and a more slowly developing antagonist effect (14, 15). The agonist effect results from (R)-roscovitine specifically binding to activated Ca V 2 channels to slow channel closing (14, 15), which results in a significant enhancement of action potential induced calcium influx (14). The antagonist effect appears to result from (R)-roscovitine preferentially enhancing occupancy of a "resting" inac...

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confidence: 75%

Section: (S)-roscovitine Does Not Affect L-channel Activation-wementioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation

Yarotskyy

Gao

et al. 2010

Journal of Biological Chemistry

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“…18 The literature data on zone 2 analogues were similarly very limited, as shown for compounds 4, 5, and 6 [e.g., (R)-olomoucine II]. 8,12 The former two trisubstituted N-6 amine analogues were devoid of any activity, suggesting that a hydrogen atom was required at N-6. Because the phenol group in 6 was able to substitute for roscovitine's benzene ring in zone 2 with minimal loss of activity, we concluded that zone 2 was amenable to further modifications.…”

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Synthesis and Biological Evaluation of a Selective N- and P/Q-Type Calcium Channel Agonist

Liang

Tarr

Bravo‐Altamirano

et al. 2012

ACS Med. Chem. Lett.

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The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (R)-roscovitine on Ca 2+ channels inspired the development of structural analogues as a potential treatment for motor nerve terminal dysfunction. On the basis of a versatile chlorinated purine scaffold, we have synthesized ca. 20 derivatives and characterized their N-type Ca 2+ channel agonist action. Agents that showed strong agonist effects were also characterized in a kinase panel for their off-target effects. Among several novel compounds with diminished cdk activity, we identified a new lead structure with a 4-fold improved N-type Ca 2+ channel agonist effect and a 22-fold decreased cdk2 activity as compared to (R)-roscovitine. This compound was selective for agonist activity on N-and P/Q-type over L-type calcium channels.

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Therapeutic Potential of N-Type Voltage-Gated Ca2+ Channel

Mohan

Pandey²,

Mungalpara³

2011

Ion Channels and Their Inhibitors

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The separation of antagonist from agonist effects of trisubstituted purines on CaV2.2 (N‐type) channels

Cited by 18 publications

References 52 publications

Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation

Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation

Synthesis and Biological Evaluation of a Selective N- and P/Q-Type Calcium Channel Agonist

Therapeutic Potential of N-Type Voltage-Gated Ca2+ Channel

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