Synthesis of new 2-(aminomethyl)-4-phenylpyrrolo[1,2-a]quinoxalines and their preliminary in-vivo central dopamine antagonist activity evaluation in mice

In the search for antipsychotic agents that are not associated with extrapy ramidal side effects, efforts have been focused on finding selective D-4-re ceptor antagonists and investigating their pharmacology. Our laboratory has developed a synthesis program for new pyrroloquinoxalines with therapeutic potential. We have described the synthesis of some new pyrroloquinoxalines with substituted arylpiperazino or aryltetrahydropyrido chain at position 3 of the quinoxaline ring (2-(4-phenylpiperazin-1-ylmethyl)-4-phenylpyrrolo [1,2-a]quinoxalinium oxalate (3a), 2-[4-(2-methoxyphenyl)piperazin-1-ylmet hyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3b), 2-[4-(3-trifluoromet hylphenyl)piperazin-1-ylmethyl] -4-phenylpyrrolo[1,2-a]quinoxalinium oxalat e (3c), 2- [4-(4-chlorophenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]q uinoxalinium oxalate (3d), 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-4-phenylp yrrolo[ 1,2-a]quinoxalinium oxalate (3e), and 2-(4-phenyl-1,2,3,6-tetrahydr opyridin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3f)). A preliminary pharmacological study of these products was conducted using c limbing behaviour induced by apomorphine (2.5 mg kg(-1), s.c.) in mice. The derivatives were administered intraperitoneally 30 min before apomorphine. Haloperidol, chlorpromazine and clozapine were used as references. Among this series, 3b, 3e and 3f revealed a central dopamine antagonist act ivity. The most active derivative was 3b, which exhibited a profile relativ ely close to clozapine.