New tetrahydrobenzindoles as potent and selective 5-HT7 antagonists with increased In vitro metabolic stability

Abstract Chemical modifications of compound 1 (DR4004), a potent, selective antagonist of the 5-HT 7 receptor, were conducted with the aim of improving its metabolic stability. Halogenation of putative sites of oxidative metabolism afforded compounds 7 – 10 , which retained high affinity and selectivity for the 5-HT 7 receptor, and showed increased in vitro metabolic stability. Compound 10 (DR4485) showed oral bioavailability, and should be a useful tool for evaluating the therapeutic potential of 5-HT 7 antagonists.