Ketone isosteres have been investigated in a series of pyrido[2,3-b]indoles (α-carbolines). The incorporation of ring fusion into α-carbolines to produce the rigid quinindoline nucleus provides a GABAA modulator with both increased potency and a longer duration of action. 4-Amino-2,9-dimethyl-9H-pyrido[2,3-b]indole-3-carboxylic acid, ethyl ester 1 is a GABAA modulator which showed good potential for the treatment of anxiety disorders. However, further biological evaluation revealed that esters such as 1 were relatively short acting in vivo with a duration of action of between one and two hours in the Geller-Seifter behavioural model of anxiety2 (see Table 2). Studies undertaken3 to determine the metabolic fate of 1 in rodents revealed that the major site of metabolism was the carboxylic ester which was cleaved to the corresponding acid 2, which was biologically inactive. Some N-9 demethylation was also observed. It was reasoned that replacement of the 3-carboxylic ester functionality with an appropriate alkyl ketone should provide a metabolically stable isostere. Molecular modelling studies (see footnote in References and Notes Section) indicated that intramolecular hydrogen bonding of the 4-amino nicotinoate moiety of 1 stabilises a low energy conformation, which was confirmed by spectroscopic analysis4. This gives a carbonyl "in plane" hypothesis for a possible preferred active conformation. Therefore, cyclisation to produce a tetracyclic lactone or ketone should give a rigid analogue which would mimic this favoured low energy conformation.