Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics

Dibenzo- and benzindolo-azecines represent a class of potential neuroleptics. To characterize the effectiveness at the dopamine and 5-HT 2A -receptor representative structures were synthesized and tested by radio ligand binding studies, in vivo and in vitro studies. Neuroleptic potency and the risk of side effects of the prodrug 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-yl isobutyrate, an ester derivative of the most promising azecine 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404), was tested in vivo concerning conditioned avoidance response inhibition, locomotor activity and triggering of catalepsy vs. haloperidol as a reference. Also ester hydrolysis was examined using porcine liver esterase to thereby obtain an indication of the stability of the prodrug in vivo. An HPLC method was developed for purity control and determination of octanol/water-distribution coefficients. It has been shown that the tested substances in their efficacy are comparable to haloperidol and risperidone, but the therapeutic index in most cases is larger. Esterification as a prodrug principle leads to significantly prolonged effectiveness.