title: Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.
abstract: We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K. michael_russell@merck.com
authors.forename: Michael G N
authors.initials: MG
authors.lastname: Russell
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carling
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Frances A
authors.initials: FA
authors.lastname: Bromidge
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Peter
authors.initials: P
authors.lastname: Hunt
authors.forename: Catherine
authors.initials: C
authors.lastname: Isted
authors.forename: Matt
authors.initials: M
authors.lastname: Lucas
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Andrew
authors.initials: A
authors.lastname: Mitchinson
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Moore
authors.forename: Robert
authors.initials: R
authors.lastname: Narquizian
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Macaulay
authors.forename: David
authors.initials: D
authors.lastname: Thomas
authors.forename: Sally-Anne
authors.initials: SA
authors.lastname: Thompson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005260:Female; D058785:GABA-A Receptor Agonists; D006801:Humans; D008958:Models, Molecular; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000819:agonists / Q000502:physiology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000502:physiology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D058785:GABA-A Receptor Agonists; D010793:Phthalazines; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014230:Triazoles