Molecular Actions of (<i>S</i>)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

Fleck, Mark W.

doi:10.1124/jpet.102.033886

Cited by 25 publications

(13 citation statements)

References 14 publications

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“…However, noncompetitive modulation has been demonstrated in many systems (e.g., Maelicke and Albuquerque, 2000;Levandoski et al, 2003;Broad et al, 2006). Likewise, SEP-174559 inhibits rat ␣3␤4 noncompetitively, but without the voltage dependence expected for a channel blocker (Fleck, 2002), which was also observed for clozapine block of ␣7 receptors (Singhal et al, 2007). We are intrigued by the possibility that disparate ligands act through a common type of binding site.…”

Section: Nicotinic Receptor Potentiation By Improved Gating 473mentioning

confidence: 99%

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Wu¹,

Smith²,

Sine³

et al. 2008

Mol Pharmacol

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We studied allosteric potentiation of rat ␣3␤2 neuronal nicotinic acetylcholine receptors (nAChRs) by the anthelmintic compound morantel. Macroscopic currents evoked by acetylcholine (ACh) from nAChRs expressed in Xenopus laevis oocytes increase up to 8-fold in the presence of low concentrations of morantel (Յ10 M); the magnitude of the potentiation depends on both agonist and modulator concentrations. It is noteworthy that the potentiated currents exceed the maximum currents achieved by saturating (millimolar) concentrations of agonist. Studies of macroscopic currents elicited by prolonged drug applications (100 -300 s) indicate that morantel does not increase ␣3␤2 receptor activity by reducing slow (Ն1 s) desensitization. Instead, using outside-out patch-clamp recordings, we demonstrate that morantel increases the frequency of single-channel openings and alters the bursting characteristics of the openings in a manner consistent with enhanced channel gating; these results quantitatively explain the macroscopic current potentiation. Morantel is a very weak agonist alone, but we show that the classic competitive antagonist dihydro-␤-erythroidine inhibits morantel-evoked currents noncompetitively, indicating that morantel does not bind to the canonical ACh binding sites.nAChRs mediate rapid synaptic transmission throughout the central and peripheral nervous systems and are implicated in a wide range of important pathologic conditions, the most pervasive of which is nicotine addiction (e.g., Berrettini and Lerman, 2005). With recent advances in high-resolution structure determination (Brejc et al

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Section: Nicotinic Receptor Potentiation By Improved Gating 473mentioning

confidence: 99%

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Wu¹,

Smith²,

Sine³

et al. 2008

Mol Pharmacol

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“…93). Subsequently, a closer examination of the Senantiomer of the N-desmethyl metabolite showed that it possesses pharmacological activity by binding better to GABA A receptors possessing the g2 subunit (Fleck, 2002). Nevertheless, after administration of zopiclone, neither the N-oxide nor desmethyl metabolites are detected in plasma (Fernandez et al, 1993), and Pharmacologically Active Metabolites therefore, it is unlikely that any drug-related effect in vivo can be attributed to metabolites.…”

Section: Drugs With Metabolites That Possess Target Potency But Comentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

138

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“…However, another report showed little subunit selectivity for zopiclone and reported mixed affinities for zaleplon on ␣ subunits depending upon which ␥ subunits they were combined with (Damgen and Luddens, 1999). Electrophysiological recordings were used to determine the K d of (R,S)-zopiclone from kinetics (K d ϭ k off /k on ) using a single concentration of zopiclone (20 M) (Fleck, 2002). GABA A receptors containing ␣1 subunits have been shown to mediate the sedative effects of diazepam (Rudolph et al, 1999;Low et al, 2000;McKernan et al, 2000) and zolpidem .…”

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confidence: 99%

Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABA_AReceptors

Petroski¹,

Pomeroy²,

Das³

et al. 2006

J Pharmacol Exp Ther

114

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Indiplon (NBI 34060) is a novel pyrazolopyrimidine currently in development for the treatment of insomnia. We have previously shown that indiplon exhibits high-affinity binding to native GABA A receptors from rat brain and acts as a positive allosteric modulator of GABA A receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABA A receptor ␣ subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents from recombinant rodent GABA A receptors expressed in human embryonic kidney 293 cells. Indiplon potentiated the GABA-activated chloride current in recombinant GABA A receptors in a dose-dependent and reversible manner and was approximately 10-fold selective for ␣1 subunit-containing receptors over GABA A receptors containing ␣2, ␣3, or ␣5 subunits. The EC 50 values were 2.6, 24, 60, and 77 nM for ␣1␤2␥2, ␣2␤2␥2, ␣3␤3␥2, and ␣5␤2␥2 receptors, respectively. Indiplon was approximately 10 times more potent than zolpidem and zopiclone and Ͼ100 times more potent than zaleplon. Moreover, indiplon, up to 1 M, did not potentiate GABA A receptors composed of ␣4␤2␥2 and ␣6␤2␥2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.GABA is the major inhibitory neurotransmitter in the mammalian central nervous system (Macdonald and Olsen, 1994). Drugs that enhance inhibitory neurotransmission include benzodiazepines, barbiturates, and general anesthetics and are used therapeutically as sedative-hypnotics, anxiolytics, antiepileptics, muscle relaxants, and anesthetics. These drugs target the GABA A receptor, an ion channel that selectively passes chloride when gated by the binding of GABA. Chloride influx serves to hyperpolarize or stabilize a negative resting membrane potential, making the neuron resistant to excitation.The GABA A receptor is a hetero-oligomeric complex composed of five transmembrane spanning subunits from sixteen different genes, ␣(1-6), ␤(1-3), ␥(1-3), ␦, ⑀, , and (Barnard et al., 1998;Korpi et al., 2002;Whiting, 2003). In most neurons, two ␣ subunits, two ␤ subunits, and one ␥ subunit form the typical GABA A receptor (Chang et al., 1996;Tretter et al., 1997). The ␦, ⑀, , and subunits have some reported selective functions but are not yet fully understood. Theoretically, there are thousands of possible subunit combinations, but a limited number of subtype combinations have been found in native systems with ␣1␤2␥2, ␣2␤3␥2, and ␣3␤3␥2 being the most abundant (Whiting, 2003). The assembly of ␣, ␤, and ␥ subunits is required to produce functional GABA A receptors that exhibit all of the pharmacological properties of native GABA A receptors. Benzodiazepine binding occurs at the interface between ␣ and ␥2 subunits (Wieland et al., 1992). GABA elicits chloride currents in recombinant GABA A receptors composed of only ␣ and ␤ subunits, but these currents are not potentiated by benzodiazepines (Schofield et al., 1987).The diversity of subunits and...

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Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

Cited by 25 publications

References 14 publications

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABA_AReceptors

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Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

Cited by 25 publications

References 14 publications

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABAAReceptors

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Product

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Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABA_AReceptors