New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics: Chemistry and pharmacological evaluation

A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulf onyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepine s were synthesized and evaluated in pharmacological models for their potent ial clozapine-like properties. In receptor binding assays, the 2-TfO analog ues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of th e dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M-1 receptor affinity. Introduct ion of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a simil ar binding profile as that of clozapine including having M1 receptor affini ty. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities, In behavioral studies performed to indicat e the potential antipsychotic efficacy and the propensity to induce EPS, 2- TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 p o for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indic ating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >5 0 sc for 9e, respectively), thus implicating a more favorable therapeutic r atio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neurole ptics such as haloperidol and isoclozapine. Furthermore, compound 18a was a lso demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation mo del. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analo gues of 11-piperazinyldibenzazepines are promising candidates as clozapine- like atypical antipsychotics with low propensity to induce EPS.