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.[1] Pagoclone belongs to the class of nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures. It was never commercialised.
It binds with roughly equivalent high affinity (0.7–9.1 nM) to the benzodiazepine binding site of human GABAAreceptors containing either an α1, α2, α3 or α5 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.[2][3] In contrast to zopiclone, pagoclone produces anxiolytic effects with little sedative or amnestic actions at low doses (0.3mg to 1.2mg per day).[4]
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, 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.[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 of diazepam and 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 a stammerer's speech fluency,[8] but research for this application was discontinued following disappointing results in Phase II clinical trials.
Synthesisedit
Pagoclone and pazinaclone both contain an isoindolone structural motif
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'.
^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. PMID 16430927. S2CID 12090552.
^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. PMID 15926867. S2CID 22793644.
^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. PMID 12871032.
^Nutt DJ (May 2006). "Alcohol alternatives--a goal for psychopharmacology?". Journal of Psychopharmacology. 20 (3): 318–320. doi:10.1177/0269881106063042. PMID 16574703. S2CID 44290147.
^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. PMID 15986186. S2CID 35569523.
^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. PMID 16702891. S2CID 33351598.
^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. PMID 20075648. S2CID 29633149.
April 15, 2024
pagoclone, anxiolytic, agent, from, cyclopyrrolone, family, related, better, known, drugs, such, sleeping, medication, zopiclone, synthesized, french, team, working, rhone, poulenc, rorer, belongs, class, nonbenzodiazepines, which, have, similar, effects, olde. 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 amp Rorer S A 1 Pagoclone belongs to the class of nonbenzodiazepines which have similar effects to the older benzodiazepine group but with quite different chemical structures It was never commercialised PagocloneClinical dataATC codenoneIdentifiersIUPAC name 2 7 chloro 1 8 naphthyridin 2 yl 3 5 methyl 2 oxohexyl isoindolin 1 oneCAS Number133737 32 3 YPubChem CID131664ChemSpider116335 YUNII38VAG2SA33KEGGD02616ChEMBLChEMBL2104745 NChemical and physical dataFormulaC 23H 22Cl N 3O 2Molar mass407 90 g mol 13D model JSmol Interactive imageSMILES Clc1nc2nc ccc2cc1 N4C O c3ccccc3C4CC O CCC C CInChI InChI 1S C23H22ClN3O2 c1 14 2 7 10 16 28 13 19 17 5 3 4 6 18 17 23 29 27 19 21 12 9 15 8 11 20 24 25 22 15 26 21 h3 6 8 9 11 12 14 19H 7 10 13H2 1 2H3 YKey HIUPRQPBWVEQJJ UHFFFAOYSA N Y N Y what is this verify It binds with roughly equivalent high affinity 0 7 9 1 nM to the benzodiazepine binding site of human GABAA receptors containing either an a1 a2 a3 or a5 subunit It is a partial agonist at a1 a2 and a5 containing GABAA receptors and a full agonist at receptors containing an a3 subunit In rats 5 hydroxypagoclone was identified as a major metabolite This metabolite has a considerably greater efficacy at the a1 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 little sedative or amnestic actions at low doses 0 3mg to 1 2mg per day 4 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 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 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 of diazepam and 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 a stammerer s speech fluency 8 but research for this application was discontinued following disappointing results in Phase II clinical trials Synthesis editPagoclone and pazinaclone both contain an isoindolone structural motif nbsp Pagoclone synthesis U S patent 4 960 779Reaction 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 editBretazenil Stuttering Basal ganglia GABAReferences 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 PMID 16430927 S2CID 12090552 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 PMID 15926867 S2CID 22793644 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 PMID 12871032 Nutt DJ May 2006 Alcohol alternatives a goal for psychopharmacology Journal of Psychopharmacology 20 3 318 320 doi 10 1177 0269881106063042 PMID 16574703 S2CID 44290147 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 PMID 15986186 S2CID 35569523 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 PMID 16702891 S2CID 33351598 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 PMID 20075648 S2CID 29633149 Retrieved from https en wikipedia org w index php title Pagoclone amp oldid 1215334091, wikipedia, wiki, book, books, library,
