N-aryl-N'-benzylpiperazines as potential antipsychotic agents

Article abstract of DOI:10.1021/jm00021a010

N¹-(2-Alkoxyphenyl)piperazines additionally containing an N⁴-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) test predictive of clinical antipsychotic activity and in in vitro receptor- binding assays. Certain of the compounds display high affinity for the D₂, 5-HT(1A), and α₁-adrenergic receptors. Structures bearing acyclic amide, lactam, and imide fuctionalities display good biological activity, with a preference for the 1,3-disubstituted phenyl ring relative to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible position of hydantoin attachment was investigated (e.g., substitution at N¹, N³, and C⁵). The hydantoin involving attachment to N¹ (24) was found to have good biological activity, whereas those hydantoins with attachment to N³ or C⁵ (22, 23, and 25) were inactive. Several of the smaller acetylated derivatives (30 and 33) have fair in vivo activity, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the D₂ receptor (65 nM) as well as excellent in vivo activity. Benzylamino compounds display (viz. 27 and 35-38) moderate CAR activity but have surprising receptor affinity, often greater than those of comparable structures bearing a carbonyl (36 vs 7). Benzyl and benzhydryl alcohol compounds 40-48 are more active than amino structures 27 and 35-38 and also exhibit excellent in vivo activity in the CAR test with modest D₂ and 5-HT(1A) receptor binding.