Pagoclone

Pagoclone
Systematic (IUPAC) name
2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one
Identifiers
CAS Number 133737-32-3 YesY
ATC code None
PubChem CID 131664
ChemSpider 116335 YesY
UNII 38VAG2SA33 YesY
ChEMBL CHEMBL2104745 N
Chemical data
Formula C23H22ClN3O2
Molar mass 407.893 g/mol
 NYesY (what is this?)  (verify)

Pagoclone is an anxiolytic drug from the cyclopyrrolone family, related to better-known drugs such as the sleeping medication zopiclone. It was synthesized by a French team working for Rhone-Poulenc & Rorer S.A.[1] It is one of a relatively recently developed class of medicines known as the nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures.

Pagoclone was originally developed as an anti-anxiety drug, but never commercialised. It is a partial agonist acting at GABAA receptors in the brain. In contrast to zopiclone, pagoclone produces anxiolytic effects with little or no sedative or amnestic actions at low doses.[2] This is because pagoclone is a subtype-selective drug which binds primarily to the α2/α3 subtypes of the GABAA receptor which are responsible for the anti-anxiety effects of drugs of this kind, but has relatively little efficacy at the α1 subtype which produces the sedative and memory loss effects.[3]

Prof. David Nutt has suggested pagoclone as a possible base from which to make a better social drug, as it produces the positive effects of alcohol, such as relaxation and sociability, but without also causing the negative effects like aggression, amnesia, nausea, loss of coordination and liver damage. Its effect can be quickly reversed by the action of flumazenil, which is already used as an antidote to benzodiazepine overdose.[4]

Nutt has published studies[5] praising the potential of pagoclone which were financed by Indevus which holds the patents to the pharmaceutical and is, as of Spring 2006, seeking funding for a possible production of the compound. The significance of this is undetermined, but 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 and it would also be expected to be somewhat safer due to its relatively weaker sedative effects,[6] but development of pagoclone as a commercial drug would still be unlikely due to concerns about abuse.

Pagoclone is also being trialed as a drug to improve a stammerer's speech fluency.[7]

Synthesis

Pagoclone and pazinaclone are both isoindolone

Pagoclone synthesis: U.S. Patent 4,960,779

Reaction of 2-Amino-7-chloro-1,8-naphthyridine with phthalic anhydride 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'.

See also

References

  1. ↑ 2-amino naphthyridine derivative, its preparation and its use US 5498716
  2. ↑ Atack, JR (Aug 2003). "Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site". Current Drug Targets. CNS and Neurological Disorders 2 (4): 213–32. doi:10.2174/1568007033482841.
  3. ↑ Atack, JR (May 2005). "The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics". Expert Opinion on Investigational Drugs 14 (5): 601–18. doi:10.1517/13543784.14.5.601.
  4. ↑ Nutt DJ (2006). "For "Critique and Commentaries" section of the Journal of Psychopharmacology: Alcohol alternatives - a goal for psychopharmacology?". Journal of Psychopharmacology 20 (3): 318–320. doi:10.1177/0269881106063042. PMID 16574703.
  5. ↑ Lingford-Hughes A; et al. (2005). "A proof-of-concept study using [11C]flumazenil PET to demonstrate that pagoclone is a partial agonist". Psychopharmacology 180 (4): 1–3. doi:10.1007/s00213-005-0060-1. PMID 15986186.
  6. ↑ de Wit H, Vicini L, Haig GM, Hunt T, Feltner D. Evaluation of the abuse potential of pagoclone, a partial GABAA agonist. Journal of Clinical Psychopharmacology. 2006 Jun;26(3):268-73.
  7. ↑ Maguire, G; Franklin, D; Vatakis, NG; Morgenshtern, E; Denko, T; Yaruss, JS; Spotts, C; Davis, L; Davis, A; Fox, P; Soni, P; Blomgren, M; Silverman, A; Riley, G (February 2010). "Exploratory randomized clinical study of pagoclone in persistent developmental stuttering: the EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study.". Journal of Clinical Psychopharmacology 30 (1): 48–56. doi:10.1097/jcp.0b013e3181caebbe. PMID 20075648. Retrieved 6 April 2013.
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