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Diazipine and [3H]diazipine were synthesized as new 1,4-dihydropyridine photoaffinity ligands containing a phenyldiazirine group. After simple high performance liquid chromatography separation, both compounds were purified in good overall yields. [3H]Diazipine (21.2 Ci/mmol) was synthesized in two steps from commercially available [3H]ethanolamine. Diazipine competitively inhibited [3H]PN200-110 binding to the calcium channel of cardiac membranes with high affinity.
We have developed two novel 3-phenyl-3-trifluoromethyldiazirinyl bis-glucose derivatives to investigate the properties of the adipocyte glucose transporter GLUT4. These compounds were substituted by electron-withdrawing (iodo and nitro) groups on the aromatic ring of 3-phenyl-3-trifluoromethyldiazirine photophore and were found to be more photosensitive than compounds without such substituents. The compounds were used as inhibitors of insulin-stimulated glucose transport activity in order to assess half-maximal inhibition or relative affinity values for GLUT4. The affinities were found to be 60-130 times higher than the parent compound D-glucose. Because of the increased photo-reactivity and high affinity these compounds will be useful in studies directed at further elucidation of GLUT4 function.
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Rats injected i.p. with AF64A at a dose of 1/3 to 11/25 LD50 showed transient signs of motor disturbance such as ataxia, squatting down and respiratory distress and also longer lasting signs consisting of adipsia, aphagia and loss of body weight. Twenty-four hours after a single injection with AF64A (129 mumol/kg), ACh contents in the cerebral cortex, hippocampus and striatum decreased significantly, and the content in the cerebral cortex still remained at a lowered level even 10 days after injection. When rats received AF64A i.p. with an initial dose of 129 mumol/kg and nine consecutive daily doses of 12.9 mumol/kg and thereafter they were kept with no medication for at least 20 days, the ACh contents in the three brain regions were still significantly reduced. ACh release by electrical stimulation or K+, but not spontaneous release, was significantly reduced in the AF64A treated rats. The T-maze spontaneous alternation behavior in rats treated with AF64A was impaired. The present results indicate that AF64A administered i.p. can induce a long lasting defect in central cholinergic transmission.
Effects of 1-methyl-2-(beta-naphthyl)-aziridine (250059-S), which possesses characteristic tranquilizing actions on levels of blood glucose and liver glygogen, and on adrenaline release from the adrenal gland were studied in rats. While there was no elevation of blood glucose, a decrease of liver glycogen was detected after an s.c. injection of 250059-S (5 or 25 mg/kg). Marked decrease of adrenaline content in adrenal glands was observed 2 hours after subcutaneous administration of 50 mg/kg of this compound. This result is consistent with the marked adrenaline secretion from the adrenal gland into adrenal-venous blood after injection of 25 mg/kg or more of 250059-S. In splanchnicotomized rats, however, 250059-S-induced adrenaline release was not clearly observed. Pretreatment with 250059-S, prevented adrenaline-induced hyperglycemia. 250059-S, at doses of 10 and 25 mg/kg, elevated the plasma insulin level to about twice that of the control. The 250059-S-induced depletion of liver glycogen was not completely blocked by adrenal demedullation, although it completely disappeared with pretreatment with 10 mg/kg of propranolol. In conclusion, 250059-S causes hypersecretion of adrenaline from the adrenal glands through excitation of the splanchnic nerves, though it causes no elevation of blood glucose, mainly because of its direct or indirect blocking action on adrenaline hyperglycemia.
To assess the effects of pH on the cytotoxicity of carboquone (CQ), use was made of the mouse tail skin and HeLa cells in culture. CQ had the most potent cytotoxic effect at pH 6 rather than at pH7 or 8. Regarding the interaction between 14C-CQ and HeLa cells, both the intracellular accumulation of free 14C-CQ and the ratio of bound 14C-CQ to total 14C-CQ uptake were enhanced at pH6. Among the fractionated biomolecules of DNA, RNA and protein, DNA was the most active in binding CQ, under the same conditions of pH. The 14C-CQ binding to nucleic acids at pH 6 was more apparent than was the binding to protein. Thus, the enhancement of CQ cytotoxicity at low pHs is probably due to an increase in the intracellular accumulation of free CQ as well as to an enhanced reactivity of CQ with DNA, within the ranges of a lower pH.
Ethylcholine aziridinium ion (AF64A), a putative cholinotoxin, was administered into the cerebroventricles of rats, and the effects on learning behaviors were observed. AF64A caused the impairment of learning acquisition in both passive and active avoidance responses. Physostigmine, a cholinesterase inhibitor, antagonized these changes at the doses of 0.03 to 0.1 mg/kg. Our behavioral study may indicate that the central cholinergic system might play a role in AF64A-induced impairment.
The effects of intracerebroventricular (ICV) injection of ethylcholine aziridinium ion (AF64A) (3 nmole/2 microliter, each lateral ventricule), a putative selective cholinotoxin, on learning behaviors and choline acetyltransferase (ChAT) activity were studied in rats. AF64A-treated rats (AF64A-rat) exhibited deficient performance in a passive avoidance task and a delayed alternation task in the T-maze, but demonstrated superior avoidance response in a two-way shuttle avoidance task. These changes in learning behaviors were associated with the selective decrease of hippocampal ChAT activity. Physostigmine (0.1 mg/kg, i.p.) significantly improved the retention latency of AF64A-rats in the passive avoidance task. AF64A-rats receiving physostigmine (0.2 mg/kg, i.p.) exhibited a slight but not significant improvement of performance in the delayed alternation task in the T-maze. These findings suggested that ICV injection of AF64A may be useful for producing an experimental amnesia model with hippocampal cholinergic hypofunction like Senile dementia of the Alzheimer type (SDAT), if appropriate learning tests are selected.
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Three stable free radicals have been prepared which are akin to 5-aziridino-2,4-dinitrobenzamide (CB 1954); these compounds all contain a nitroxide function. The metabolism and excretion of two such compounds in mice has been monitored by electron spin resonance (ESR) spectroscopy and compared with that of the simpler nitroxide, 4-keto-2,2,6,6-tetramethylpiperidino-1-oxyl (tempone).
In severe cases of e.o. IV to VI combined treatment with Cyclosporin A and corticosteroids is most effective whereas Ciamixon alone appears to be less effective. Patients who received Ciamexon some time after termination of Cyclosporin A treatment showed slight ophthalmological improvement or stabilization of the status (judged after short time of therapy). Patients with e.o. III (IV), treated ineffectively with only corticosteroids before, showed a tendency of improvement under Ciamexon treatment.
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