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.

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.

A series of 5-acyl-3-substituted-benzofuran-2(3H)-ones and their respective ring-opened o-hydroxy acids were synthesized. The antiinflammatory activity was evaluated in terms of their ability to improve adjuvant induced arthritis in rats. Their effect on the production of both cyclooxygenase (CO) and lipoxygenase (LO) metabolites of arachidonic acid in guinea pig peritoneal polymorphonuclear neutrophils (PMNs) was also examined. No correlation between the antiinflammatory activity and increasing stability of the lactones could be found. The degree of activity in general shown by the benzofuranones was similar to that of their corresponding o-hydroxy acids. This, coupled with the evidence from studies on opening of the lactone ring, suggests an in vivo transformation of the former into the latter. Benzofuranones displayed a dual inhibition of CO and LO products, while a moderate reduction in CO metabolites was shown by their acids.

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.

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.

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