New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics: chemistry and pharmacological evaluation.
A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. 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 indicate 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 po 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 indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also 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 model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.
Liao
Y
Y
Department of Medical Biochemistry, University of Göteborg, Box 440, SE-405 30 Göteborg, Sweden. y.liao@arm.rug.nl
Venhuis
B J
BJ
Rodenhuis
N
N
Timmerman
W
W
Wikström
H
H
Meier
E
E
Bartoszyk
G D
GD
Böttcher
H
H
Seyfried
C A
CA
Sundell
S
S
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D010879:Piperazines; D043643:Receptor, Muscarinic M1; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin