Synthesis and pharmacological evaluation of a series of 4-piperazinylpyrazolo[3,4-b]- and -[4,3-b][1,5]benzodiazepines as potential anxiolytics.

The synthesis and pharmacological evaluation of a series of pyrazolo[b][1,5]benzodiazepines are described. Some of the 4-piperazinyl-2,10-dihydropyrazolo[3,4-b][1,5]benzodiazepine derivatives demonstrated potent anxiolytic activity in the three-part operant anticonflict test in rats. Compounds 21 and 30 were more active than the clinically effective anxiolytic chlordiazepoxide in releasing conflict-suppressed behavior. This study shows a dissociation of the anxiolytic and antidopaminergic activities found in the thieno- and dibenzodiazepine derivatives flumezapine and clozapine, respectively. Examples of the three other dihydropyrazolo[b][1,5]benzodiazepine ring systems are described and evaluated for comparison and were found to be less active.

Synthesis and pharmacological evaluation of CNS activities of [1,2,3]triazolo[4,5-b][1,5]-, imidazolo[4,5-b][1,5]-, and pyrido[2,3-b][1,5]benzodiazepines. 10-Piperazinyl-4H-1,2,3-triazolo[4,5-b][1,5]benzodiazepines with neuroleptic activity.

The synthesis of [1,2,3]triazolo[4,5-b][1,5]-, imidazolo[4,5-b][1,5]-, and pyrido[2,3-b][1,5]benzodiazepines is described. The antidopaminergic and anticholinergic activities of the compounds have been examined by the respective in vitro [3H]spiperone and [3H]QNB receptor binding assay. The neuroleptic potential has been further evaluated in terms of their ability to produce hypothermia and catalepsy in mice and a conditioned avoidance response in rats. Only compounds from the triazolobenzodiazepine series show antipsychotic potential. The lack of activity in the imidazolo- and pyridobenzodiazepine series indicates that the basicity of the heteroarene moiety may be determinant for activity.

Effects of conformationally restricted 4-piperazinyl-10H-thienobenzodiazepine neuroleptics on central dopaminergic and cholinergic systems.

The levels of antidopaminergic and anticholinergic activities of neuroleptics, 4-piperazinyl-10H-thienobenzodiazepines, are modulated by imposing steric impedence to the piperazine ring. The optimum situation in favor of the anticholinergic action is reached in compound 5, 2,3-dimethyl-7-fluoro-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, where a maximum activity (equivalent to hyoscine), as measured by the [3H]QNB receptor binding assay, is obtained. The structure-activity relationships found highlight the importance of certain spatial dispositions of the distal piperazine nitrogen (electron lone pair) with respect to the tricyclic system. The evidence for molecular topography of these compounds is presented from X-ray, NMR, and other physical data. The conformational aspects for correspondence to the relevant receptors are discussed.

4-Piperazinyl-10H-thieno[2,3-b][1,5]benzodiazepines as potential neuroleptics.

A series of 4-substituted 10H-theino[2,3-b][1,5]benzodiazepines has been synthesized. These compounds have been assessed for their ability to block a conditioned avoidance response (CAR) and to produce catalepsy in rats and have been compared with several typical and atypical neuroleptics. The compounds which inhibit CAR at doses which produce no catalepsy are believed to cause less extrapyramidal side effects in the clinic. A number of compounds (9, 12, 17, 29, and 34) show potent neuroleptic activity, yet maintain a favorable separation of activity on these two parametrs. Three 5-piperazinyl-10H-thieno[2,3-b][1,4]benzodiazepine derivatives (46-48) analogous to compounds in the [1,5] series have been prepared for comparison and were found to be inactive.

Adamantane and protoadamantanealkanamines as potential anti-Parkinson agents.

The synthesis of 2-halo-1-adamantanemethanamines, 4-protoadamantanemethanamines, and 4-protoadamantaneamines is described. The anti-Parkinson activity of these amines in terms of reversal of reserpine-induced catalepsy in rats has been evaluated and compared with amantadine. 2-Bromo- and 2-chloro-1-adamantanemethanamines are shown to be twice as active as amantadine.