N-ARYL-N'-BENZYLPIPERAZINES AS POTENTIAL ANTIPSYCHOTIC AGENTS

N-1-(2-Alkoxyphenyl)piperazines additionally containing an N-4-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) te st predictive of clinical antipsychotic activity and in in vitro recep tor-binding assays. Certain of the compounds display high affinity for the D-2, 5-HT1A, and al-adrenergic receptors. Structures bearing acyc lic amide, lactam, and imide fuctionalities display good biological ac tivity, with a preference for the 1,3-disubstituted phenyl ring relati ve to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible posi tion of hydantoin attachment was investigated (e.g., substitution at N -1, N-3, and C-5). Th, hydantoin involving attachment to N-1 (24) was found to have good biological activity, whereas those hydantoins with attachment to N-3 Or C-5 (22, 23, and 25) were inactive. Several of th e, smaller acetylated derivatives (30 and 33) have fair in vivo activi ty, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the Da receptor (65 nM) as well a s excellent in vivo activity. Benzylamino compounds display (viz. 27 a nd 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 acti ve than amino structures 27 and 35-38 and also exhibit excellent in vi vo activity in the CAR test with modest D-2 and 5-HT1A receptor bindin g.