Pagoclone: Difference between revisions

{{short description|Chemical compound}}

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| ChEMBL = 2104745

| KEGG = D02616

'''Pagoclone''' is an [[anxiolytic]] agent 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.<ref>{{cite patent | inventor = David-Comte MT, Roussel G | assign1 = Rhone Poulenc Rorer SA | title = 2-Amino naphthyridine derivative, its preparation and its use | country = US | number = 5498716 | gdate = 12 March 1996 | postscript = . }}</ref> Pagoclone belongs to the class of [[nonbenzodiazepine]]s, which have similar effects to the older [[benzodiazepine]] group, but with quite different [[chemical structure]]s. It was never commercialised.

It binds with roughly equivalent high affinity (0.7–9.1 nM) to the benzodiazepine [[binding site]] of human [[GABA A receptor|GABA_A]] [[receptor (biochemistry)|receptors]] containing either an α1, α2, α3 or α5 [[Protein subunit|subunit]]. It is a [[partial agonist]] 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]]. This metabolite has a considerably greater [[efficacy]] at the α1 subtype than the parent compound and was shown to have significant anxiolytic-like activity and to produce sedation.<ref name="pmid16430927">{{cite journal | vauthors = Atack JR, Pike A, Marshall G, Stanley J, Lincoln R, Cook SM, Lewis RT, Blackaby WP, Goodacre SC, McKernan RM, Dawson GR, Wafford KA, Reynolds DS | display-authors = 6 | title = The in vivo properties of pagoclone in rat are most likely mediated by 5'-hydroxy pagoclone | journal = Neuropharmacology | volume = 50 | issue = 6 | pages = 677–689 | date = May 2006 | pmid = 16430927 | doi = 10.1016/j.neuropharm.2005.11.014 | s2cid = 12090552 }}</ref><ref>{{cite journal | vauthors = Atack JR | title = The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics | journal = Expert Opinion on Investigational Drugs | volume = 14 | issue = 5 | pages = 601–618 | date = May 2005 | pmid = 15926867 | doi = 10.1517/13543784.14.5.601 | s2cid = 22793644 }}</ref> In contrast to zopiclone, pagoclone produces anxiolytic effects with little [[sedative]] or [[amnestic]] actions at low doses (0.3mg to 1.2mg per day).<ref>{{cite journal | vauthors = Atack JR | title = Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 2 | issue = 4 | pages = 213–232 | date = August 2003 | pmid = 12871032 | doi = 10.2174/1568007033482841 }}</ref>

The pharmacologist [[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 (drug)|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]].<ref>{{cite journal | vauthors = Nutt DJ | title = Alcohol alternatives--a goal for psychopharmacology? | journal = Journal of Psychopharmacology | volume = 20 | issue = 3 | pages = 318–320 | date = May 2006 | pmid = 16574703 | doi = 10.1177/0269881106063042 | s2cid = 44290147 }}</ref> Nutt has published studies<ref>{{cite journal | vauthors = Lingford-Hughes A, Wilson SJ, Feeney A, Grasby PG, Nutt DJ | title = A proof-of-concept study using [11C]flumazenil PET to demonstrate that pagoclone is a partial agonist | journal = Psychopharmacology | volume = 180 | issue = 4 | pages = 789–791 | date = August 2005 | pmid = 15986186 | doi = 10.1007/s00213-005-0060-1 | s2cid = 35569523 | author-link = Anne Lingford-Hughes }}</ref> 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]] and it would also be expected to be somewhat safer due to its relatively weaker sedative effects,<ref name="pmid16702891">{{cite journal | vauthors = de Wit H, Vicini L, Haig GM, Hunt T, Feltner D | title = Evaluation of the abuse potential of pagoclone, a partial GABAA agonist | journal = Journal of Clinical Psychopharmacology | volume = 26 | issue = 3 | pages = 268–73 | date = June 2006 | pmid = 16702891 | doi = 10.1097/01.jcp.0000218983.61683.96 | s2cid = 33351598 }}</ref> but development of pagoclone as a commercial drug would still be unlikely due to concerns about abuse.{{citation needed|date=July 2022}}

Pagoclone was trialed as a drug to improve a [[stutter|stammerer]]'s speech fluency,<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Exploratory randomized clinical study of pagoclone in persistent developmental stuttering: the EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study | journal = Journal of Clinical Psychopharmacology | volume = 30 | issue = 1 | pages = 48–56 | date = February 2010 | pmid = 20075648 | doi = 10.1097/jcp.0b013e3181caebbe | s2cid = 29633149 }}</ref> but research for this application was discontinued following disappointing results in Phase II clinical trials.

==Synthesis==

Pagoclone and [[pazinaclone]] both contain an isoindolone structural motif

[[File:Pagoclone synthesis.png|thumb|center|501px|Pagoclone synthesis: {{US patent|4960779}}]]

Reaction of [[phthalic 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 ==

== References ==

{{Anxiolytics}}

{{GABAAR PAMs}}

[[Category:Anxiolytics]]

[[Category:Chloroarenes]]

[[Category:GABAA receptor positive allosteric modulators]]

[[Category:Isoindolines]]

[[Category:Naphthyridines]]

[[Category:Isopentyl compounds]]