当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > 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.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Russell MG,Carling RW,Atack JR,Bromidge FA,Cook SM,Hunt P,Isted C,Lucas M,McKernan RM,Mitchinson A,Moore KW,Narquizian R,Macaulay AJ,Thomas D,Thompson SA,Wafford KA,Castro JL

doi

10.1021/jm040883v

keywords:

subject

Has Abstract

pub_date

2005-03-10 00:00:00

pages

1367-83

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

48

pub_type

杂志文章

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