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Cyclopyrrolones
Cyclopyrrolones
Cyclopyrrolones
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Skeletal formula of the parent compound, cyclopyrrolone

Cyclopyrrolones are a family of hypnotic and anxiolytic nonbenzodiazepine drugs with similar pharmacological profiles to the benzodiazepine derivatives.

Although cyclopyrrolones are chemically unrelated to benzodiazepines, they function via the benzodiazepine receptor of neurotransmitter GABA.[1] The best-known cyclopyrrolone derivatives are zopiclone (Imovane) and its active single-enantiomer component, eszopiclone (Lunesta), which are used to treat insomnia, and have a known potential for abuse. Other cyclopyrrolones include:

References

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Cyclopyrrolones

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Cyclopyrrolones are a class of drugs that function as hypnotics and anxiolytics, featuring a distinct unrelated to benzodiazepines while targeting the GABA_A receptor complex to enhance inhibitory neurotransmission in the . The class is exemplified by , the first developed member introduced in the , and its active S-enantiomer, , which is approved for clinical use in multiple countries. These agents are primarily prescribed for the short- or long-term management of , offering effects with a pharmacological profile of high efficacy and low toxicity compared to traditional benzodiazepines. Pharmacologically, cyclopyrrolones act as positive allosteric modulators at GABA_A receptors, binding to sites adjacent to the recognition site and increasing chloride ion conductance to produce , , , and pronounced effects. Unlike , which bind directly to the canonical site, cyclopyrrolones exhibit activity with varying affinities for α1, α2, α3, and α5 subunits, potentially leading to differential potencies in versus anxiolysis across animal models. , a , reaches peak plasma concentrations within 1-2 hours, has a of approximately 5-6 hours (extended to about 9 hours in the elderly), and undergoes hepatic metabolism primarily via without accumulating active metabolites. shares similar kinetics but demonstrates higher potency as the pharmacologically active , with around 80%; high-fat meals may slow absorption (increasing T_max slightly and reducing C_max by ~21%) without affecting overall exposure (AUC). In clinical practice, cyclopyrrolones effectively reduce sleep latency, increase total sleep time, and decrease nighttime awakenings in patients with primary or comorbid , with notably approved by the FDA for extended use beyond the typical 2-4 weeks recommended for other hypnotics. They are generally well-tolerated, with common adverse effects including a bitter metallic , , and mild gastrointestinal upset; however, rare but serious complex sleep behaviors, such as , have been reported, leading to a FDA ., but lower incidences of next-day psychomotor impairment, dependence, and withdrawal symptoms than benzodiazepines. Despite their advantages, caution is advised in patients with hepatic impairment or those taking inhibitors, as these can prolong exposure and enhance sedative risks.

Chemistry

Chemical structure

Cyclopyrrolones constitute a class of compounds primarily featuring a core bicyclic pyrrolo[3,4-b]pyrazine ring system in their prototype members, which incorporates a fused and ring with a pyrrolone moiety indicated by the 7-oxo substitution. This scaffold forms the foundational structure for their pharmacological activity, distinguishing them as non-benzodiazepine hypnotics. While exemplifies this framework, other cyclopyrrolones such as and suriclone incorporate structural variations, such as modified fused rings, while retaining activity at the GABA_A receptor. In the general structure of prototype cyclopyrrolones like zopiclone, key substituents include a chloropyridyl group, typically 5-chloropyridin-2-yl, attached at the 6-position and a piperazine carboxylate moiety, often 4-methylpiperazine-1-carboxylate, at the 5-position. The prototype compound, zopiclone, exemplifies this framework with the IUPAC name (RS)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate, highlighting the base scaffold without variations specific to individual derivatives. This molecular architecture sets cyclopyrrolones apart from , which are defined by a fused ring and a seven-membered diazepine ring, emphasizing the non-fused, heterocyclic nature of the prototype cyclopyrrolone system and its absence of the diazepine component.

Synthesis

The synthesis of cyclopyrrolone compounds, such as , typically begins with the initial condensation of precursors, notably pyrazine-2,3-dicarboxylic anhydride, and an amine derivative like 2-amino-5-chloropyridine to form a key intermediate, 3-(5-chloro-2-pyridyl)carbamoyl-pyrazine-2-carboxylic acid. This step establishes the foundation for the bicyclic pyrrolo[3,4-b]pyrazine core characteristic of prototype cyclopyrrolones. A critical cyclization follows, where the amide intermediate is treated with under conditions to form the 5,7-dioxo-6,7-dihydropyrrolo[3,4-b]pyrazine , analogous to an intramolecular that closes the pyrrolone ring. Selective reduction of one carbonyl using potassium borohydride then yields the 5-hydroxy-7-oxo intermediate, introducing the at the 6-position. For substituent introduction, the chloropyridyl group is incorporated via the starting 2-amino-5-chloropyridine, where the is pre-installed, though alternative routes may involve post-condensation at the ring for analogous derivatives. The final step involves esterification of the with 1-chlorocarbonyl-4-methylpiperazine in the presence of a base like in , forming the and affording racemic . This is crucial for the moiety's attachment, enhancing the compound's pharmacological profile. SA first described the synthesis of in a 1972 patent and developed a scalable industrial process in the based on this multi-step sequence, enabling commercial manufacturing starting in 1986. Later variants of the process, such as those described in subsequent patents, optimized yields and safety by replacing hazardous bases like with milder alternatives such as .

Pharmacology

Mechanism of action

Cyclopyrrolones exert their pharmacological effects primarily through positive allosteric modulation of GABA_A receptors, a family of ligand-gated channels that mediate inhibitory in the . These compounds bind to a specific allosteric site on the GABA_A receptor, enhancing the affinity of the receptor for its endogenous agonist, (GABA), without directly activating the channel. This modulation increases the frequency and duration of channel opening in response to GABA, thereby amplifying inhibitory signaling. The primary representative, , displaces radiolabeled benzodiazepines such as [³H]flunitrazepam from their binding site and potentiates GABA binding, as demonstrated in radioligand binding assays on rat membranes. The for cyclopyrrolones is located at the extracellular interface between the α and γ subunits of the GABA_A receptor, homologous to the classical recognition site. This α(+)/γ(–) interface involves key residues from the principal face of the α subunit and the complementary face of the γ2 subunit, allowing cyclopyrrolones to stabilize a conformation that favors GABA-induced channel gating. Structural studies using cryo-electron microscopy have confirmed this site for related modulators, showing how binding induces subtle conformational changes that propagate to the channel pore. Unlike some other non- hypnotics, cyclopyrrolones such as exhibit little to no selectivity among GABA_A receptor subtypes containing different α subunits (e.g., α1 vs. α2 or α3), binding with comparable affinity across benzodiazepine receptor phenotypes BZ1 and BZ2. Upon binding, cyclopyrrolones enhance GABA-evoked chloride (Cl⁻) influx through the receptor channel, leading to neuronal hyperpolarization and reduced excitability. This is achieved by increasing the conductance (g) of the GABA-gated Cl⁻ current, as described by the simplified equation for the ionic current: IGABA=g⋅(ECl−Vm)I_{\text{GABA}} = g \cdot (E_{\text{Cl}} - V_m) where IGABAI_{\text{GABA}} is the GABA-induced current, EClE_{\text{Cl}} is the chloride reversal potential (typically around -70 mV), and VmV_m is the membrane potential. The modulation boosts g without altering EClE_{\text{Cl}}, resulting in greater hyperpolarization for a given GABA concentration. Electrophysiological studies in recombinant systems and brain slices show this enhancement varies by compound; for instance, suriclone fully potentiates muscimol-stimulated ³⁶Cl⁻ uptake similar to diazepam, while zopiclone displays lower efficacy. A key distinction from classical benzodiazepines lies in the binding and efficacy profile of cyclopyrrolones. Unlike benzodiazepines, whose binding is positively modulated by GABA, cyclopyrrolone binding to the GABA_A receptor is insensitive to GABA presence, indicating a more rigid interaction at the allosteric site. Certain cyclopyrrolones, such as , exhibit partial agonism with reduced intrinsic efficacy compared to full agonists like , as evidenced by their ability to antagonize maximal benzodiazepine effects in chloride flux assays and lower potency in some models. This partial agonism may contribute to a reduced propensity for tolerance development, though the clinical significance remains under investigation.

Pharmacodynamics

Cyclopyrrolones elicit sedation and anxiolysis primarily through positive allosteric modulation of GABA_A receptors, enhancing GABA-mediated chloride conductance and promoting neuronal hyperpolarization in the . This results in reduced neuronal excitability, facilitating sleep onset and reducing anxiety without the pronounced muscle relaxation observed with benzodiazepines at equivalent hypnotic doses. The therapeutic profile emphasizes high hypnotic efficacy with lower intrinsic activity at receptor sites associated with motor impairment, leading to decreased and myorelaxation compared to full agonists. For instance, compounds like and suriclone demonstrate sedative effects via competitive interaction at the , but with partial that limits excessive inhibition of motor pathways. Cyclopyrrolones display subtype selectivity within the GABA_A receptor family, with predominant affinity for α1-containing receptors that drive hypnotic effects such as . Binding to α2- and α3-containing subtypes varies across the class and contributes to properties; for example, exhibits comparable affinity for α1, α3, and α5 subunits, while derivatives like show enhanced α2/α3 selectivity for anxiolysis with reduced . In animal models, hypnotic potency is characterized by dose-dependent responses, with ED50 values for or potentiation around 5-10 mg/kg in , as seen in locomotor suppression and synergy tests for . This range highlights effective at doses below those causing significant motor disruption. Secondary pharmacodynamic effects include mild activity, though with lower potency than benzodiazepines; , for example, protects against pentylenetetrazol-induced seizures with an ED50 of 1.2 mg/kg (oral) in mice, higher than diazepam's approximately 1 mg/kg. Myorelaxant effects are similarly subdued, often requiring doses exceeding 50 mg/kg in models to achieve significant inhibition.

Pharmacokinetics

Cyclopyrrolones, such as and its enantiomer , exhibit high oral ranging from 70% to 80%, with rapid absorption from the leading to peak plasma concentrations (T_max) within 1 to 2 hours after administration. This quick onset is facilitated by their lipophilic nature, allowing efficient crossing of the blood-brain barrier to exert effects. Food may slightly delay absorption but does not significantly alter overall exposure. Distribution of cyclopyrrolones is extensive, with a approximately 1.4 L/kg, reflecting wide tissue penetration including the brain. Plasma protein binding is moderate, around 45-59%, which contributes to their availability for pharmacological action. Metabolism occurs primarily in the liver via enzymes, predominantly , with some involvement of and CYP2C8, leading to inactive or less active metabolites such as N-oxide and N-desmethyl derivatives. The elimination is approximately 5 hours for racemic zopiclone and 6 hours for eszopiclone in healthy adults, though it may prolong slightly in the elderly. Elimination is mainly renal, with less than 10% of the parent excreted unchanged in and the majority (about 75-80%) as inactive metabolites. Due to their short half-lives, cyclopyrrolones do not accumulate with short-term, once-daily use in individuals with normal hepatic and renal function.

Medical uses

Insomnia treatment

Cyclopyrrolones, such as and , are primarily indicated for the management of . is approved for short-term use, with treatment durations typically limited to 2-4 weeks to reduce the potential for tolerance and dependence. is approved by the FDA for both short- and long-term treatment of without a specified duration limit. These agents effectively address both sleep onset and maintenance difficulties by modulating GABA_A receptors, leading to improved overall sleep quality without substantially altering normal sleep architecture in short-term use. Clinical evidence from randomized controlled trials demonstrates that cyclopyrrolones significantly outperform in reducing sleep latency by 15-30 minutes, based on both polysomnographic and subjective measures. For instance, at 3 mg has been shown to decrease subjective sleep latency by up to 25 minutes and objective latency by about 14 minutes. Meta-analyses of early studies on from the and , including trials by Billiard et al. (1987) and Mamelak et al. (1983), further confirm superiority over for sleep maintenance, with reductions in nocturnal awakenings and wake time after sleep onset. A supports these findings, indicating zopiclone's efficacy in decreasing awakenings and wake after sleep onset in older adults with . Recommended dosing emphasizes the lowest effective dose to optimize benefits while minimizing risks; for , this is typically 3.75-7.5 mg taken immediately before bedtime, with reduced doses (up to 5 mg maximum) for elderly patients. dosing ranges from 1-3 mg, with 2-3 mg commonly used for adults based on guideline recommendations. In comparison to other Z-drugs like , cyclopyrrolones show similar efficacy in shortening sleep latency but exert broader influences on sleep stages, such as augmenting stage 2 sleep, reducing stage 1 sleep, and occasionally enhancing , which may contribute to better sleep consolidation.

Anxiety treatment

Cyclopyrrolones, particularly investigational agents such as pagoclone, were explored for anxiety management via partial agonism at the α2 and α3 subunits of GABA_A receptors, which underpin anxiolytic actions, while displaying partial agonism at the α1 subunit to minimize excessive sedation. This subtype selectivity enables anxiolysis with a more favorable therapeutic window than nonselective agonists. Preclinical evidence supports the utility of cyclopyrrolones, demonstrating efficacy in anxiety models with potency differences relative to endpoints. For , early clinical trials in (GAD) have shown reductions in anxiety symptoms; a phase II, double-blind, -controlled study of 157 patients with baseline (HAM-A) scores ≥18 reported a mean HAM-A decrease of -14.2 with the 0.6 mg dose after 8 weeks, versus -10.1 for (p=0.03). No cyclopyrrolones are approved for anxiety indications. Development of for anxiety was discontinued in the early 2000s. , approved solely for , sees occasional for anxiety but lacks first-line status owing to its hypnotic predominance and sedating bias. In differentiation from benzodiazepines, cyclopyrrolones exhibit lower abuse liability, evidenced by preclinical models where partial agonism yields reduced self-administration and dependence compared to full agonists. For specifically, animal and early human data indicate diminished dependence risk alongside benefits.

Adverse effects

Common side effects

Common side effects of cyclopyrrolones, such as and , are generally mild and transient, often related to their modulation of GABA_A receptors leading to . These effects typically occur shortly after administration and resolve upon discontinuation. One of the most frequently reported side effects is , characterized by a bitter or metallic taste in the mouth, affecting approximately 10% of users and up to 34% of those taking higher doses of (3 mg). This unpleasant taste arises from the presence of the drug or its metabolites in , with higher saliva concentrations correlating with increased intensity. Drowsiness and are also prevalent, manifesting as next-day residual or with an incidence of 8-10% for and 1-7% for in -treated patients. These effects can impair alertness and coordination, particularly in the elderly or with doses exceeding 7.5 mg. Gastrointestinal disturbances, including dry mouth and , occur in 2-7% of users, with dry mouth reported in 3-7% of zopiclone cases and in about 2-5%. These symptoms are usually self-limiting but may contribute to discomfort during treatment. Cognitive effects, such as mild , are noted at higher doses (e.g., 7.5 mg or more of ), affecting memory formation during the drug's peak action period, though incidence is low (less than 5%) and reversible. Rare but serious complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, have been reported with cyclopyrrolones. These can result in serious injury and should be discontinued if they occur. Patients are advised to ensure at least 7-8 hours of sleep and avoid alcohol or other CNS depressants.

Long-term risks

Prolonged use of cyclopyrrolones, such as and , can lead to the development of tolerance and , typically emerging after 2-4 weeks of continuous administration. Tolerance manifests as diminished hypnotic efficacy, necessitating higher doses to achieve the same sleep-inducing effects, while dependence may result in withdrawal symptoms upon discontinuation, including rebound , anxiety, and in severe cases, seizures or hallucinations. These risks are attributed to the drugs' agonism at GABA_A receptors, which parallels but is generally less severe than that observed with benzodiazepines. Cyclopyrrolones possess a moderate abuse potential, leading to their classification as Schedule IV controlled substances under the U.S. , reflecting evidence of reinforcing effects in preclinical models and reports of misuse in humans. Although their abuse liability is lower than that of benzodiazepines based on epidemiological data and case reports, chronic users have demonstrated patterns of escalation, diversion, and polydrug , particularly among individuals with histories of substance use disorders. Some observational studies have suggested a possible association between long-term use of cyclopyrrolone and other receptor agonists and increased risk of or in older adults, though causality is not established and results may be confounded by underlying . Rare cases of have been reported with cyclopyrrolone use, including acute manifesting as elevated transaminases and , though these events are infrequent and often resolve upon drug cessation. Additionally, as cyclopyrrolones are primarily metabolized by the enzyme, co-administration with potent inhibitors such as can significantly increase systemic exposure, heightening the risk of adverse effects and toxicity.

History

Development

In the early 1970s, pharmaceutical researchers at initiated a program to develop novel psychotherapeutic agents as alternatives to benzodiazepines, motivated by growing concerns over the latter's potential for and withdrawal symptoms that had become evident during the . This effort responded to epidemiological reports of benzodiazepine-related withdrawal issues, prompting a shift toward compounds with similar and properties but reduced risk of tolerance and dependence. The cyclopyrrolone class emerged from this initiative, characterized by a unique unrelated to benzodiazepines or barbiturates, yet capable of modulating the GABA_A receptor complex. A pivotal occurred in 1972 with the patenting of the synthesis of a prototype at Rhône-Poulenc (US3862149A), followed by initial pharmacological screening that demonstrated its high affinity for the binding site on GABA_A receptors, eliciting sedative- effects without the broader seen in barbiturates. These early screenings confirmed zopiclone's ability to enhance GABA-mediated chloride influx, distinguishing it as the first compound in the cyclopyrrolone family with a targeted hypnotic profile. Preclinical advances in the late and throughout the involved extensive that further delineated the efficacy of cyclopyrrolones, revealing a potency for inducing with a favorable compared to barbiturates, which often produced excessive respiratory depression and lethality at higher doses. In and cats, zopiclone prototypes shortened latency and increased non-REM duration while preserving arousal thresholds, effects mediated through selective allosteric modulation rather than direct channel opening as with barbiturates. These findings solidified the class's potential as a safer option for management, paving the way for subsequent clinical exploration.

Regulatory approval

Cyclopyrrolones as a class have received varying regulatory approvals worldwide, primarily for short-term treatment of , with and its being the most advanced. was first approved in in 1986 by the French regulatory authority for short-term management of and has since been authorized in numerous countries, including , , and much of and , though it remains unavailable in the United States due to the preference for its active . In contrast, received U.S. (FDA) approval on December 15, 2004, under the brand name Lunesta for the treatment of sleep onset and maintenance in adults. An application for centralized (EMA) approval of (as Lunivia) was submitted in 2007 but withdrawn in 2009 prior to final decision, as the EMA deemed it sufficiently similar to the already approved without sufficient new benefits. Other cyclopyrrolones, such as and suriclone, remain investigational and have not achieved regulatory approval for clinical use. , initially developed by and later by and Indevus Pharmaceuticals, advanced to Phase III trials for but was discontinued in June 2002 due to insufficient efficacy; subsequent Phase II trials for were halted in 2006 for similar reasons. Later, in the 2000s, was investigated for by Indevus Pharmaceuticals and Teva Pharmaceutical Industries, advancing to Phase II trials, but development was discontinued around 2010 due to disappointing results. Suriclone, also from early development, underwent preclinical and early clinical studies in the for effects but was discontinued without progressing to later-stage trials or approval, likely due to limited differentiation from benzodiazepines. Regulatory guidelines emphasize limited use of approved cyclopyrrolones to mitigate risks of dependence and tolerance. The (WHO) recommends and similar non-benzodiazepine hypnotics for short-term treatment not exceeding 4 weeks, with ongoing monitoring for abuse potential. In alignment with broader management standards, professional organizations such as the (AASM) advise short-term pharmacologic intervention with agents like only after nonpharmacologic therapies fail, prioritizing durations of 4–5 weeks or less. In the United States, is classified as a Schedule IV under the , reflecting its accepted medical use alongside a low potential for abuse relative to Schedule III agents.

Notable compounds

Zopiclone and eszopiclone

is a of the R- and S-enantiomers of a cyclopyrrolone , serving as a hypnotic primarily indicated for short-term treatment of . It was developed and first introduced to the market in 1986 by (now part of ). Pharmacokinetically, exhibits rapid absorption with a terminal elimination of approximately 5 hours, facilitating its use for initiation without significant next-day residual effects in most patients. Common brand names include Imovane, which is widely recognized in regions where the drug is approved. Eszopiclone represents the active S-enantiomer isolated from the racemic , providing a purer profile by concentrating the pharmacologically potent responsible for enhanced GABA_A receptor modulation and effects. The U.S. approved in December 2004 for the treatment of , marking it as the first explicitly indicated for longer-term use. Its show a slightly extended terminal elimination of about 6 hours compared to , supporting improved sleep maintenance, while formulations address the bitter aftertaste associated with the racemate, resulting in a less pronounced metallic or bitter sensation upon administration. Clinically, both compounds demonstrate comparable efficacy in reducing sleep onset latency by 20-30% in controlled trials, with eszopiclone distinguishing itself through evidence from phase III studies supporting safe and effective use for up to 6 months in patients with chronic insomnia, unlike the typical short-term restriction for zopiclone. This extended approval for eszopiclone reflects its favorable tolerability profile in long-duration trials, where sustained improvements in sleep efficiency were observed without significant rebound insomnia upon discontinuation. Regarding availability, has been off-patent for years and is accessible as a generic medication in and , where it is commonly prescribed under various brand names for transient . In contrast, remained under patent protection in the United States until 2014, with generic versions entering the market starting in 2014 following the expiration of key patents.

Pagoclone and suriclone

is a cyclopyrrolone derivative developed as a selective partial agonist at the GABAA receptor's benzodiazepine site, intended for the treatment of anxiety disorders with reduced risk of , tolerance, and withdrawal compared to full agonists like . Originally pursued by and later by Indevus Pharmaceuticals, entered phase II/III clinical trials for in the late 1990s, but discontinued development in 2002 due to strategic priorities. Indevus advanced it for generalized anxiety and , showing preliminary efficacy in reducing panic attacks in a small crossover trial of 14 patients with DSM-IV , where 0.1 mg three times daily over two 2-week periods decreased mean weekly attacks from 5.8 to 3.6 (p=0.05 vs. baseline; 4.3 on , p=0.14 vs. baseline, no significant difference vs. ). In the same study, no significant benzodiazepine-like side effects were observed, supporting its partial agonist profile. Further evaluation in healthy volunteers assessed neuropsychological impacts at doses of 0.15–0.60 mg twice daily for 7 days, revealing only mild, transient impairments in learning and memory on day 1 at higher doses (0.30 mg and 0.60 mg), which resolved by day 6, with no effects on or motor speed. This suggests minimal cognitive , enhancing its potential as an . Indevus also explored for persistent developmental , reporting promising phase II results in that improved speech fluency, but development halted in amid company focus shifts and lack of commercialization. Suriclone (RP 31,264), developed by in the early 1980s, represents an earlier cyclopyrrolone that binds with high affinity to central receptors and modulates transmission, as evidenced by reduced striatal homovanillic acid levels in rats and enhanced presynaptic inhibition in cats, without direct activation. It demonstrated clinical efficacy in across doses of 0.1–0.4 mg three times daily, outperforming in a 4-week multicenter trial of 54–59 outpatients (DSM-III-R criteria) on improvements, with no dose-response differences among active suriclone arms. Compared to (5 mg three times daily), suriclone showed equivalent efficacy but superior tolerability, with lower rates of drowsiness and other adverse events, particularly at 0.1–0.2 mg doses matching safety profiles. Neurologic assessments confirmed suriclone's distinct profile from benzodiazepines; at 0.8 mg, it induced unique effects like and ocular movements absent in 10 mg, while sharing benefits at therapeutic doses of 1.2–3.6 mg daily, with action lasting 6–8 hours. Despite these positive findings, suriclone was not commercialized, likely due to the competitive market dominated by benzodiazepines during its development era. Both and suriclone highlight the cyclopyrrolone class's versatility for non-sedating anxiety management, though neither achieved regulatory approval.

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