The in vivo properties of pagoclone in rat are most likely mediated by 5'-hydroxy pagoclone.
The cyclopyrrolone pagoclone binds with roughly equivalent high affinity (0.7-9.1nM) to the benzodiazepine binding site of human recombinant GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 subunit. However, whereas it was a partial agonist at alpha1-, alpha2- and alpha5-containing GABA(A) receptors, pagoclone was a full agonist at receptors containing an alpha3 subunit. In the rat elevated plus maze assay pagoclone (3mg/kg) had significant anxiolytic-like activity but at all three doses tested (0.3, 1 and 3mg/kg p.o.) it produced a significant reduction in the total distance travelled. This sedative-like effect was confirmed in rat chain-pulling and spontaneous locomotor assays. Surprisingly, in the plasma and brain samples derived from the elevated plus maze assay, the major metabolite of pagoclone, 5'-hydroxy pagoclone, was present at 10-20-fold higher concentrations relative to the parent compound. In order to establish whether this metabolite might have pharmacological activity, we measured its affinity and efficacy profile and found that both were comparable to those of pagoclone with the exception that efficacy at the alpha1 subtype was considerably greater for 5'-hydroxy pagoclone compared with the parent. This metabolite had significant anxiolytic-like activity in the elevated plus maze but at these same doses (0.3-3mg/kg p.o.) also produced sedation. It is therefore likely that in rats 5'-hydroxy pagoclone mediates the majority of the pharmacological actions following pagoclone administration.
Atack
John R
JR
Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. john.atack@merck.com
Pike
Andy
A
Marshall
George
G
Stanley
Jo
J
Lincoln
Rachael
R
Cook
Susan M
SM
Lewis
Richard T
RT
Blackaby
Wesley P
WP
Goodacre
Simon C
SC
McKernan
Ruth M
RM
Dawson
Gerard R
GR
Wafford
Keith A
KA
Reynolds
David S
DS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics; D054833:Isoindoles; D007536:Isomerism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009287:Naphthyridines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D021122:Protein Subunits / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D018757:GABA Modulators; D007211:Indoles; D054833:Isoindoles; D009287:Naphthyridines; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014316:Tritium; C076721:RP 59037; C447412:pagoclone; D005442:Flumazenil