Pagoclone
 | |
| Clinical data | |
|---|---|
| ATC code |
|
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C23H22ClN3O2 |
| Molar mass | 407.90g·mol−1 |
| 3D model (JSmol) | |
| |
| |
  (what is this?)(verify) | |
Pagocloneis ananxiolyticagent from thecyclopyrrolonefamily, related to better-known drugs such as the sleeping medicationzopiclone.It was synthesized by a French team working for Rhone-Poulenc & Rorer S.A.[1]Pagoclone belongs to the class ofnonbenzodiazepines,which have similar effects to the olderbenzodiazepinegroup, but with quite differentchemical structures.It was never commercialised.
It binds with roughly equivalent high affinity (0.7–9.1 nM) to the benzodiazepinebinding siteof humanGABAAreceptorscontaining either an α1, α2, α3 or α5subunit.It is apartial agonistat 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 majormetabolite.This metabolite has a considerably greaterefficacyat the α1 subtype than the parent compound and was shown to have significant anxiolytic-like activity and to produce sedation.[2][3]In contrast to zopiclone, pagoclone produces anxiolytic effects with littlesedativeoramnesticactions at low doses (0.3mg to 1.2mg per day).[4]
The pharmacologistDavid Nutthas suggested pagoclone as a possible base from which to make a better social drug, as it produces the positive effects ofalcohol,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 offlumazenil,which is already used as an antidote tobenzodiazepine overdose.[5]Nutt has published studies[6]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 ofdiazepamand it would also be expected to be somewhat safer due to its relatively weaker sedative effects,[7]but development of pagoclone as a commercial drug would still be unlikely due to concerns about abuse.[citation needed]
Pagoclone was trialed as a drug to improve astammerer's speech fluency,[8]but research for this application was discontinued following disappointing results in Phase II clinical trials.
Synthesis
[edit]Pagoclone andpazinacloneboth contain an isoindolone structural motif
Reaction ofphthalic anhydride[85-44-9] (1) with 2-Amino-7-chloro-1,8-naphthyridine[15944-33-9] (2) with leads to the corresponding phthalimide. Selective reduction of one of the imide carbonyl groups give the corresponding alcohol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one [55112-38-4] (3). Reaction with the carbanion from Ethyl 5-methyl-3-oxohexanoate [57689-16-4] (4) 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'. The product of this step is Ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxoheptanoate, PC9891305 (5).
See also
[edit]References
[edit]- ^US 5498716,David-Comte MT, Roussel G, "2-Amino naphthyridine derivative, its preparation and its use", issued 12 March 1996, assigned to Rhone Poulenc Rorer SA.
- ^Atack JR, Pike A, Marshall G, Stanley J, Lincoln R, Cook SM, et al. (May 2006). "The in vivo properties of pagoclone in rat are most likely mediated by 5'-hydroxy pagoclone".Neuropharmacology.50(6): 677–689.doi:10.1016/j.neuropharm.2005.11.014.PMID16430927.S2CID12090552.
- ^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): 601–618.doi:10.1517/13543784.14.5.601.PMID15926867.S2CID22793644.
- ^Atack JR (August 2003). "Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site".Current Drug Targets. CNS and Neurological Disorders.2(4): 213–232.doi:10.2174/1568007033482841.PMID12871032.
- ^Nutt DJ (May 2006). "Alcohol alternatives--a goal for psychopharmacology?".Journal of Psychopharmacology.20(3): 318–320.doi:10.1177/0269881106063042.PMID16574703.S2CID44290147.
- ^Lingford-Hughes A,Wilson SJ, Feeney A, Grasby PG, Nutt DJ (August 2005). "A proof-of-concept study using [11C]flumazenil PET to demonstrate that pagoclone is a partial agonist".Psychopharmacology.180(4): 789–791.doi:10.1007/s00213-005-0060-1.PMID15986186.S2CID35569523.
- ^de Wit H, Vicini L, Haig GM, Hunt T, Feltner D (June 2006). "Evaluation of the abuse potential of pagoclone, a partial GABAA agonist".Journal of Clinical Psychopharmacology.26(3): 268–73.doi:10.1097/01.jcp.0000218983.61683.96.PMID16702891.S2CID33351598.
- ^Maguire G, Franklin D, Vatakis NG, Morgenshtern E, Denko T, Yaruss JS, et al. (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.PMID20075648.S2CID29633149.