Edward B. Roche

Synthesis and biological activity of chloromethyl ketones of leucine enkephalin

Summary The chloromethyl ketones of leucine enkephalin and D-Ala 2 -leucine enkephalin have been synthesized and tested for biological activity in the guinea pig ileum assay. The derivatives show an increased potency in morphine-like action in comparison to the corresponding enkephalins.

Altered Activities of Hepatic and Extrahepatic Microsomal Mixed Function Oxidase Enzymes in Diabetic and Adrenalectomized Diabetic Rats

Microsomal aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin-O-deethylase (ECD) activities were determined in liver, lung and intestine of control, streptozotocin(STZ)-diabetic, and diabetic-adrenalectomized male and female rats. Hepatic cytochrome P-450 content was also determined. The diabetic state reduced hepatic AHH activity and increased ECD activity in control male rats, and failed to do so in the adrenalectomized male rats. The diabetic state increased hepatic AHH and ECD activities in the control female rats, while in the adrenalectomized female rats the activities of both enzymes were decreased compared to the control diabetic rats. STZ-induced diabetes produced a decrease in pulmonary AHH and ECD activities and increased intestinal AHH and ECD activities in both sexes. The diabetic state in the adrenalectomized rats resulted in further reduction in pulmonary AHH and ECD activities in both sexes, but failed to increase the intestinal AHH activity only in the female rat. Hepatic cytochrome P-450 contents were increased in the female but not male adrenalectomized rats when treated with STZ. The effects of STZ-induced diabetes in adrenalectomized rats on AHH, ECD and hepatic cytochrome P-450 content in liver, lung and intestine depended upon sex of animal, substrate and tissue.

Activities of hepatic and extrahepatic microsomal mixed function oxidase enzymes in diabetic and gonadectomized-diabetic rats

Abstract 1. 1. Streptozotocin (STZ)-induced diabetes results in a decrease in hepatic aryl hydrocarbon hydroxylase (AHH) activity in male rats and an increase in female rats, while hepatic 7-ethoxycoumarin 0-deethylase (ECD) activity is increased in both sexes. 2. 2. In castrated male rats, induction of the diabetic state resulted in a further decrease in hepatic AHH activity. In diabetic female rats, ovariectomy did not alter hepatic AHH or ECD activities. 3. 3. STZ-induced diabetes produced an increase in hepatic cytochrome P-450 content. The diabetic state failed to produce an increase in hepatic cytochrome P-450 content of castrated male animals, and only a small increase in castrated female rats. 4. 4. AHH and ECD activities are decreased in lungs of STZ-induced diabetic male and female rats. In diabetic-castrated rats a further decrease in pulmonary ECD activity occurs in both sexes, and in the AHH activity of female rats. 5. 5. The induction of diabetes with STZ increased intestinal AHH and ECD activities in both sexes. In diabetic-castrated rats, intestinal ECD activities were identical to the activities in diabetic male and female animals, while intestinal AHH activities were lower than the activities in diabetic animals but still significantly higher than in control animals of both sexes.

Conformational analysis of the reverse ester of acetylcholine, cholinergic potency, and cholinergic models

Abstract 1. 1. The conformational energy profile of the reverse ester of acetylcholine, a potent nicotinic agonist, was studied using EHT and PCILO molecular orbital calculations. 2. 2. The preferred conformation calculated by EHT has T1 = T2 = 180°, which is an extended molecule. 3. 3. The PCILO calculated preferred conformer has T1 = T2 = 60°, which corresponds to a folded molecule. 4. 4. The calculated preferred conformers do not match the preferred conformer given by X-ray crystallography. 5. 5. Comparison of the preferred conformations with the cholinergic potency of the reverse ester reveals that the models developed by Kier and by Chothia & Pauling for muscarinic and nicotinic activity cannot explain the activity of the reverse ester. 6. 6. A model based on the flexibility of the receptors and of the cholinergic molecules and electronic similarities in requisite atomic centers is necessary to explain the activity satisfactorily.

EFFECTS OF ESTRONE, ESTRADIOL AND ESTRIOL PRETREATMENT ON HEPATIC, LUNG, AND INTESTINAL ARYL HYDROCARBON HYDROXYLASE ACTIVITIES IN FEMALE RATS

Forty day old female rats were given 1 mg/kg estrone (E1), estradiol (E2), or estriol (E3), i.p., acutely or chronically. The data indicate that alterations of AHH activity are organ specific and depend upon the estrogen administered as well as the duration of steroid pretreatment. The differences observed may be explained on the basis of estrogen receptors.