Pagoclone is an

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...

agent from the

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 b ...

family, related to better-known drugs such as the sleeping medication

zopiclone Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases th ...

. It was synthesized by a French team working for Rhone-Poulenc & Rorer S.A. Pagoclone belongs to the class of

nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...

s, which have similar effects to the older

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

group, but with quite different

chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...

s. It was never commercialised. It binds with roughly equivalent high affinity (0.7–9.1 nM) to the benzodiazepine

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

of human GABA_A

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

containing either an α1, α2, α3 or α5

subunit Subunit may refer to: * Subunit HIV vaccine, a class of HIV vaccine *Protein subunit, a protein molecule that assembles with other protein molecules *Monomer, a molecule that may bind chemically to other molecules to form a polymer * Sub-subunit, ...

. It is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

at α1-, α2- and α5-containing GABAA receptors and a full agonist at receptors containing an α3 subunit. In rats 5′-hydroxypagoclone was identified as a major

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

. This metabolite has a considerably greater

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

at the α1 subtype than the parent compound and was shown to have significant anxiolytic-like activity and to produce sedation. In contrast to zopiclone, pagoclone produces anxiolytic effects with little

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...

or amnestic actions at low doses (0.3mg to 1.2mg per day). The pharmacologist

David Nutt David John Nutt (born 16 April 1951) is an English neuropsychopharmacologist specialising in the research of drugs that affect the brain and conditions such as addiction, anxiety, and sleep. He is the chairman of Drug Science, a non-profit w ...

has suggested pagoclone as a possible base from which to make a better social drug, as it produces the positive effects of

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

, such as relaxation and sociability, but without also causing the negative effects like aggression,

amnesia Amnesia is a deficit in memory caused by brain damage or disease,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be caused temporarily by the use ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

, loss of coordination and liver damage. Its effect can be quickly reversed by the action of

flumazenil Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines ( ...

, which is already used as an antidote to

benzodiazepine overdose Benzodiazepine overdose describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. The most common symptoms of overdose include central nervous system (CNS) depressio ...

. Nutt has published studies praising the potential of pagoclone which were financed by Indevus which was seeking funding for a possible production of the compound. The long-term safety of pagoclone has not been assessed. The abuse potential of pagoclone has been assessed as being similar to, or slightly less than that of

diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...

and it would also be expected to be somewhat safer due to its relatively weaker sedative effects, but development of pagoclone as a commercial drug would still be unlikely due to concerns about abuse. Pagoclone was trialed as a drug to improve a

stammerer Stuttering, also known as stammering, is a speech disorder in which the flow of speech is disrupted by involuntary repetitions and prolongations of sounds, syllables, words, or phrases as well as involuntary silent pauses or blocks in which the ...

's speech fluency, but research for this application was discontinued following disappointing results in Phase II clinical trials.

Synthesis

Pagoclone and pazinaclone are both isoindolone Pagoclone synthesis

Reaction of 2-Amino-7-chloro-1,8-

naphthyridine Diazanaphthalenes are a class of aromatic heterocyclic chemical compounds that have the formula C8H6N2. They consist of a naphthalene double ring in which two of the carbon atoms have been replaced with nitrogen atoms. There are ten positional isom ...

with

phthalic anhydride Phthalic anhydride is the organic compound with the formula C6H4(CO)2O. It is the anhydride of phthalic acid. Phthalic anhydride is a principal commercial form of phthalic acid. It was the first anhydride of a dicarboxylic acid to be used commer ...

leads to the corresponding phthalimide. Selective reduction of one of the imide carbonyl groups give the corresponding alcohol. Reaction with the carbanion from Ethyl 5-methyl-3-oxohexanoate leads to the product from the displacement of the hydroxyl group; 'this too may proceed via the acrylate obtained from aldol reaction of the ring opened imidal'.

References

{{GABAAR PAMs Anxiolytics Chloroarenes Cyclopyrrolones GABAA receptor positive allosteric modulators Isoindolines Ketones Lactams Naphthyridines

Synthesis

See also

References