RESUMO
OBJECTIVE: To design and synthesize brain targeting danshensu (DSS) derivatives and study their metabolism in rat plasma and brain homogenate in vitro. METHODS: Tetramethylpyrazine and its derivatives were selected as carriers to design the brain targeting danshen suderivatives. Lipid-water partition coefficient (logf), brain blood concentration ratio (BB), and P-glycopro-tein affinity of the derivatives were predicted by some calculation softwares and the better compound DT3 was chosen for the next synthesis. The degradation of DT3 and its intermediate DTI in rat plasma and brain homogenate were measured by HPLC-UV. RESULTS: Two danshensu-pyrazine ester derivatives were synthesized, ie DTI and DT3. A simultaneous determination method of DT3, DTI, and (3,5,6-trimethylpyrazine-2-yl) methanol (TMPM) in rat plasma and brain homogenate was established. The degradation of DT3 in rat plasma and brain homogenate underwent the following process; DT3→DTl→the active metabolites of DSS and TMPM. Compared with DTI, the degradation of DT3 in rat plasma slowed down. The half-lives (t1/2) of TMPM were 1.68 and 1.71 min, respectively. Also, DT3 could quickly release the active metabolitein rat brain homogenate, and the concentration of TMPM showed a steady increase with a t1/2 of 222.88 min. CONCLUSION: The danshensu-pyrazine ester derivative DT3 has an extended t1/2 in rat plasma, and it can be degraded to active metabolite quickly in rat brain homogenate.