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.
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.
Russell
Michael G N
MG
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K. michael_russell@merck.com
Carling
Robert W
RW
Atack
John R
JR
Bromidge
Frances A
FA
Cook
Susan M
SM
Hunt
Peter
P
Isted
Catherine
C
Lucas
Matt
M
McKernan
Ruth M
RM
Mitchinson
Andrew
A
Moore
Kevin W
KW
Narquizian
Robert
R
Macaulay
Alison J
AJ
Thomas
David
D
Thompson
Sally-Anne
SA
Wafford
Keith A
KA
Castro
José L
JL
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
D058785:GABA-A Receptor Agonists; D010793:Phthalazines; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014230:Triazoles