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.
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.
Street
Leslie J
LJ
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
Sternfeld
Francine
F
Jelley
Richard A
RA
Reeve
Austin J
AJ
Carling
Robert W
RW
Moore
Kevin W
KW
McKernan
Ruth M
RM
Sohal
Bindi
B
Cook
Susan
S
Pike
Andrew
A
Dawson
Gerard R
GR
Bromidge
Frances A
FA
Wafford
Keith A
KA
Seabrook
Guy R
GR
Thompson
Sally A
SA
Marshall
George
G
Pillai
Goplan V
GV
Castro
José L
JL
Atack
John R
JR
MacLeod
Angus M
AM
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
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