Preformulation studies and estimation of brain penetration for two alpidem analogues having anticonvulsant activity

The dual aim of this study was to gain insight into the potential development of two alpidem analogues 2 and 3 containing a GABA or glycine moiety and to explore the brain penetration properties accounting for their anticonvulsant effects. For these purposes, solubility, stability and brain penetration studies were performed. In contrast to that found in acidic medium, in phosphate buffer pH 7.4 compounds 2 and 3 were poorly soluble. In solution buffered at pH 7.4 compounds 2 and 3 showed half-lives of 140 and 64 h, but they were found to undergo faster cleavage in dilute rat serum at 37°C. To gain insights into the brain penetration properties of compounds 2 and 3 after intraperitoneal administration, capillary electrophoresis, semi-microbore liquid chromatography and electron spray ionization-mass spectrometry techniques were used to analyze microdialysis samples. The detection of intact compounds 2 and 3, along with the absence of acid solutes in the dialysate, lend support to a mechanism whereby the alpidem analogues 2 and 3 act as intact molecules rather than in a prodrug-type mechanism, implying that GABA and Gly, respectively, are delivered to the brain.