Fendiline inhibits L‐type calcium channels in guinea‐pig ventricular myocytes: a whole‐cell patch‐clamp study

Tripathi, O.; Schultze-Seemann, Wolfgang; Tritthart, H. A.

doi:10.1111/j.1476-5381.1993.tb13479.x

Cited by 16 publications

(12 citation statements)

References 24 publications

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“…Fendiline is a GABA B R PAM (Kerr et al 2002;Ong et al 2005) and an L-type Ca 2+ channel blocker (Nawrath et al 1998;Tripathi et al 1993), and each of these may alter substrates critical for memory maintenance. While it is clear that fendiline potentiates GABA B R signaling in vitro (Chen et al 2005;Ong and Kerr 2005), there is controversy regarding the ability of fendiline to function as a GABA B R PAM in vivo (Urwyler et al 2004); therefore, the respective contribution of fendiline acting as a GABA B R PAM or as an L-type Ca 2+ channel blocker in the current study awaits further studies with selective ligands.…”

Section: Discussionmentioning

confidence: 99%

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

2013

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Rationale Fendiline is a GABAB receptor positive allosteric modulator and L-type Ca2+ channel blocker that is safe for human use. Based on these pharmacological properties, fendiline may be useful to disrupt associative memories that can drive relapse to drug use in drug-addicted individuals. Objective The current study evaluated the potential of fendiline to inhibit the maintenance and expression of learned associations between methamphetamine (meth) and an environmental context using conditioned place preference (CPP) in rats, to model for the associative learning that occurs during drug abuse by humans. Methods Following meth conditioning (1mg/kg), fendiline (5mg/kg) was administered at various post-conditioning times to ascertain if there was a temporal window during which fendiline would be effective. Results Two once-daily injections of fendiline did not influence the maintenance of CPP regardless of the post-conditioning treatment time while 10 once-daily fendiline treatments inhibited CPP maintenance (p<0.05). Fendiline administered immediately prior to the CPP test inhibited expression of meth-induced CPP in rats with a fendiline treatment history of 10 once-daily injections (p<0.05) or those that received two injections that corresponded to the last two days of the 10 day treatment (p<0.05). Fendiline did not produce preference or aversion on its own, nor did it alter motivated motor behavior. Conclusion Maintenance and expression of meth CPP is mitigated by repeated fendiline treatments when administered during the days that precede CPP testing. Reduction in the significance of meth-associated cues can reduce relapse; therefore, fendiline may be of value for addiction therapy in abstinent, meth-addicted humans.

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Section: Discussionmentioning

confidence: 99%

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

2013

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“…Fendiline, a coronary vasodilator, belongs to a class of nonselective calcium channel blockers that displace the prototypical calcium channel antagonist fluspirilene from Lchannels with high affinity. At the cellular level, fendiline inhibits L-type calcium channels in muscle cells in vitro (64,93) and has an inhibitory effect on the calciumsensing protein calmodulin (55,69). Most importantly, it was shown to act as a calcium mobilizer in renal tubular cells, by releasing stored calcium and activating extracellular calcium entry (41).…”

Section: Pharmacologymentioning

confidence: 99%

Clinical Potential of GABA_B Receptor Modulators

Ong

Kerr

2005

CNS Drug Reviews

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Metabotropic gamma-aminobutyric acid(B) (GABAB) receptors for the major inhibitory transmitter GABA, together with metabotropic glutamate (mGLuRs) receptors, the extracellular calcium-sensing receptors (CaSRs), some V2R pheromone receptors and T1R taste receptors, belong to the family of 3 G-protein-coupled receptors (GPCRs). GABAB receptors are known to control neuronal excitability and modulate synaptic neurotransmission, playing a very important role in many physiological activities. These receptors are widely expressed and distributed in the nervous system and have been implicated in a variety of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, depression, schizophrenia and drug addiction. To form a functional receptor entity, GABAB receptors must exist as a heterodimer consisting of GABAB1 and GABAB2 receptor subtypes with two 7-transmembrane proteins, and these subunits arise from distinct genes. The GABAB1 subunit binds the endogenous ligand within its extracellular N-terminus, whilst the GABAB2 subunit is not only essential for the correct trafficking of the GABAB1 subunit to the cell surface, but is also responsible for the interaction of the receptor with its cognate G-protein. Allosteric modulation has recently been recognized as an alternative pharmacological approach to gain selectivity in drug action. It is now generally accepted that modulators acting at the allosteric sites provide a novel perspective for the development of subtype-selective agents acting at GPCRs. These agents interact with allosteric binding sites quite separate from the highly conserved agonist binding region. In this review, we present a new class of phenylalkylamines, based on the lead compound fendiline, that are potent positive potentiators of GABAB receptor-mediated function and discuss their putative clinical applications. It is proposed that these new modulators may have therapeutic value in GABAB receptor pharmacology and are capable of selectively modifying GABAB receptor function. The allosteric modulators are offering an attractive and novel means to identify new leads, that are devoid of side effects associated with GABAB receptor agonists, and may, therefore, represent a major advance in the drug discovery process.

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“…The concentration range (3-200 Ìmol/l) of fendiline that was found to increase [Ca 2+ ] i in bladder cancer cells and kidney cells has often been used by researchers to inhibit voltage-gated Ca 2+ channels in excitable cells [5][6][7][8]. Fendiline is clinically applied as an antianginal drug based on its blocking effect on L-type Ca 2+ channels.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, fendiline has been found to inhibit L-type Ca 2+ channels [6,7] and calmodulin [8]. Notably, fendiline was recently shown to act as a Ca 2+ mobilizer in renal tubular cells, by releasing stored Ca 2+ and activating external Ca 2+ influx [9].…”

Section: Introductionmentioning

confidence: 99%

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca<sup>2+</sup> and Induction of Cell Death

Jan

Huang

2001

Pharmacology

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The effect of fendiline, an antianginal drug, on cytosolic free Ca²⁺ levels ([Ca²⁺]_i) in populations of bladder female transitional carcinoma (BFTC) cells was explored using fura-2 as a Ca²⁺ indicator. Fendiline at concentrations between 3 and 200 µmol/l increased [Ca²⁺]_i in a concentration-dependent manner and the signal saturated at 100 µmol/l. The [Ca²⁺]_i signal was biphasic, with an initial rise and a slow decay. Ca²⁺ removal inhibited the Ca²⁺ signal by about half in peak amplitude. Adding 3 mmol/l Ca²⁺ increased [Ca²⁺]_i in cells pretreated with 100 µmol/l fendiline in Ca²⁺-free medium, suggesting that fendiline induced Ca²⁺ influx via capacitative Ca²⁺ entry. In Ca²⁺-free medium, pretreatment with 1 µmol/l thapsigargin (an endoplasmic reticulum Ca²⁺ pump inhibitor) to deplete the endoplasmic reticulum Ca²⁺ store inhibited most of the 100 µmol/l fendiline-induced internal Ca²⁺ release; and conversely, pretreatment with 100 µmol/l fendiline partly inhibited 1 µmol/l thapsigargin-induced Ca²⁺ release. This indicates that the major internal Ca²⁺ store of fendiline-induced [Ca²⁺]_i increases is located in the endoplasmic reticulum. The Ca²⁺ release induced by 100 µmol/l fendiline may be partly mediated by inositol 1,4,5-trisphosphate, because the [Ca²⁺]_i increase was inhibited by 50% by inhibiting phospholipase C with 2 µmol/l U73122. Fendiline (100 µmol/l) decreased cell viability by 12–44% after being added to cells for 2– 30 min. Together, the findings indicate that in BFTC cells, fendiline exerts a dual effect: mobilization of intracellular Ca²⁺ and induction of cell death.

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Fendiline inhibits L‐type calcium channels in guinea‐pig ventricular myocytes: a whole‐cell patch‐clamp study

Cited by 16 publications

References 24 publications

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

Clinical Potential of GABA_B Receptor Modulators

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca<sup>2+</sup> and Induction of Cell Death

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Fendiline inhibits L‐type calcium channels in guinea‐pig ventricular myocytes: a whole‐cell patch‐clamp study

Cited by 16 publications

References 24 publications

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

Effect of fendiline on the maintenance and expression of methamphetamine-induced conditioned place preference in Sprague–Dawley rats

Clinical Potential of GABAB Receptor Modulators

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca<sup>2+</sup> and Induction of Cell Death

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Clinical Potential of GABA_B Receptor Modulators