Synthesis of targeted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines as potential lead molecules with promising anti-breast cancer activity.

A targeted library of substituted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines (prototypes I, II and III), and structurally analogous to tamoxifen have been synthesized as a new class of anti-breast cancer agents. All the prototype molecules exhibited potential antiproliferative activity against ER + ve and ER-ve breast cancer cell lines. Dibenzo[b,f]thiepine prototypes were found to be more active. Of all the compound tested, 14b exhibited potent in-vitro antiproliferative activity at 1.33 µM and 5 µM concentration in MCF-7 and MDA-MB-231 cell lines and was devoid of any cytotoxicity in normal HEK cells even at 50 µM. Cell cycle analysis showed that the compound 14b inhibited cell proliferation due to G0/G1 arrest in MCF-7 cells. Annexin-V FITC and PI staining experiments confirmed that the cell inhibition was primarily due to apoptosis and not by necrosis, which was also supported by LDH release assay experiment. Molecular docking studies showed better binding interaction of the new dibenzo[b,f]thiepine analogue 14b with the estrogen receptor (ER) as compared to 4-hydroxy-tamoxifen and this enhanced binding might be responsible for its estrogen antagonistic activity that induces cell cycle arrest, apoptosis and inhibition of breast cancer cells.

BMY-14802 reversed the sigma receptor agonist-induced neck dystonia in rats.

To clarify clinical roles of sigma receptor binding affinity of neuroleptics, neck dystonia induced by microinjection of sigma receptor ligands and neuroleptics into rat red nucleus was investigated. DTG and (+)-3-PPP, putative sigma receptor agonists, induced neck dystonia in dose-dependent and reversible manner. Haloperidol and perphenazine induced dystonia in the same way as sigma receptor agonists, whereas zotepine and (-)-sulpiride did not. The rank order of potency in induction of dystonia and sigma receptor affinity of these compounds showed positive correlation. Although BMY-14802 has a high affinity for sigma receptors, it never produced dystonia by itself. On the other hand, combined injection of BMY-14802 with DTG attenuated DTG-induced dystonia. Therefore, it is suggested that typical neuroleptics such as haloperidol act agonistic and atypical neuroleptics such as BMY-14802 act antagonistic at rubral sigma receptors in the induction of neck dystonia.

Anti-arrhythmic effects of a new calcium antagonist, monatepil, AJ-2615, in experimental arrhythmic models [corrected].

1. To characterize the anti-arrhythmic properties of a new calcium antagonist, monatepil [corrected], AJ-2615, the preventive effects of AJ-2615 were compared with those of the existing calcium antagonists, diltiazem and verapamil, in experimental models of arrhythmia. 2. AJ-2615 (0.1-3.0 mg/kg, i.v.) suppressed ventricular arrhythmias induced by adrenaline (10 micrograms/kg, i.v.) in rats. AJ-2615 (0.1 mg/kg per min for 2 min, i.v.) also suppressed atrial tachycardia induced by aconitine (0.01% aconitine solution) in rats. 3. In these activities, AJ-2615 was comparable to or more potent than diltiazem and verapamil which are widely used for the treatment of arrhythmia. 4. In pro-arrhythmic activity, AJ-2615 was less potent than diltiazem and verapamil. 5. These results suggest that AJ-2615 would be a safer anti-arrhythmic agent, with less proarrhythmic liability than diltiazem and verapamil.

Pharmacological properties of a potent neuroleptic drug octoclothepin.

Octoclothepin, 8-chloro-1-(4-methylpiperazino)-10,11-dihydrodibenzo (b,f) thiepin, is a very potent neuroleptic drug with pronounced central antidopaminergic and antiserotonin actions. In most animal experiments, its plharmacological profile resembles that of perphenazine. Octoclothepin reveals an intensive central depressant action in a series of observational and instrumental procedures in rodents. Its active oral doses are within the range of 0.54 to 2.2 mg kg-1 in mice and of 0.1 to 4.8 mg kg-1 in rats. Octoclothepin possesses high cataleptogenic and anti-apomorphine activities in rats; it is able to exert full protection against apomorphine-induced emesis in dogs after the dose of 0.1 mg kg-1 s.c. Octoclothepin reduces some actions and toxicity of d,l-amphetamine and phenmetrazine in rodents. In the rat corpus striatum, octoclothepin in doses of 0.5 and d1.5 mg kg-1 s.c. reduces the DA level and raises the HVA and DOPAC levels significantly. Octoclothepin has antihistamine, antiserotonin and antianaphylactoid actions, it exhibits a high protection against the lethal action of adrenaline and noradrenaline in mice and rats, respectively. Acute toxicological data in mice, rats, rabbits and dogs are given. Clinical antipsychotic effectiveness of octoclothepin has been verified in a large population of psychiatric patients.

Toxicological and teratological studies of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]thiepine (zotepine), a new neuroleptic drug.

Toxicological and teratological studies of 2-chloro-11-(2-dimethylaminoethoxy)dibenzo[b,f]thiepine (zotepine) were performed in mice, rats, rabbits and dogs. There was no essential difference among mice, rats, rabbits and dogs in the acute toxicity of i.v. given zotepine. The rather small variation between intravenous and oral acute toxicity suggests the good absorption of zotepine from the gastrointestinal tract. In the subacute and chronic toxicity studies in rats, significant changes attributed to the drug were impairment of growth, alveolar proliferation in the mammary gland, decrease in uterine weight and increased number of diestrous rats. These changes were dose-dependent in the animals given 16 mg/kg or higher. Incidence of tumor in the treated groups in the 12-month study was almost the same as that in the control. In the subacute and chronic toxicity studies in dogs, abnormal quietness and abnormal gait occurred. Enlarged breasts and galactorrhea also occurred in females given 16 and 64 mg/kg in the 6-month study. Apart from these changes, one dog given 64 mg/kg had reversible hepatic dysfunction. In the teratological studies, zotepine had no adverse effects on pregnant animals and their fetuses in rats and rabbits, or reproductive performance of the F1 rats.

8-chloro-(S)- and -(R)-10-((S)-and -(R)-3'-methylethylaminopyrrolidino)- 10,11-dihydrodibenzo(b,f)thiepins. Synthesis and pharmacological studies.

The synthesis for 8-chloro-(S)- and -(R)-10-[(S)- and -(R)-3'-methylethylaminopyrrolidino]-10,11-dihydrodibenzo[b,f]thiepins is presented. The absolute configuration at position 3' of the aminopyrrolidino side chain is known from synthesis and corresponds to the asymmetric carbon atom in (S)- or (R)-aspartic acid. The absolute configuration at C-10 of the dihydrodibenzo[b,f]thiepin ring system was deduced from ORD-CD analysis coupled with degradation of partially resolved (+)-8-chloro-10-amino-10,11-dihydrodibenzo[b,f]thiepin to (+)-(S)-1,2-diphenylethylamine. The four isomers were studied in mice for their ability to block conditioned avoidance responding, antagonize oxotremorine, and act as analgetics and anticonvulsants. These compounds were found to be nonselective antagonists of histamine, acetylcholine, and BaCl2 in vitro. The compounds exerted effects similar to those of chlorpromazine. Stereoselective differences in activity between diastereoisomers, rather than between enantiomorphs, were generally observed.