title: Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site.
abstract: The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
authors.affiliation: Departments of Medicinal Chemistry, Biochemistry, and Pharmacology, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. Leslie_Street@Merck.com
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.forename: Francine
authors.initials: F
authors.lastname: Sternfeld
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jelley
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Reeve
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carling
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Moore
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Susan
authors.initials: S
authors.lastname: Cook
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: Frances A
authors.initials: FA
authors.lastname: Bromidge
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Guy R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: Sally A
authors.initials: SA
authors.lastname: Thompson
authors.forename: George
authors.initials: G
authors.lastname: Marshall
authors.forename: Goplan V
authors.initials: GV
authors.lastname: Pillai
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D005260:Female; D058785:GABA-A Receptor Agonists; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D021122:Protein Subunits / Q000819:agonists; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: C488116:3-(5-methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo(3,4-a)phthalazine; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D010793:Phthalazines; D021122:Protein Subunits; D014230:Triazoles