Aleck Borman

A-norprogesterone, an androgen antagonist.

Summary A-norprogesterone antagonizes testosterone induced accessory sex organ hypertrophy in the immature castrate male rat and comb growth stimulation in the chick. Growth of the ventral prostate, seminal vesicles, adrenals and thyroids of intact rats and the chick comb in animals not treated with androgen were significnatly reduced by administration of this compound. A-norprogesterone is not androgenic, estrogenic, anti-estrogenic, progestational or anti-progestational under the experimental conditions described.

Biological Activities of 16α, 17α Dihydroxyprogesterone Derivatives

Summary The 16α, 17α acetophenane (P-DHP) and acetone (A-DHP) derivatives of 16α, 17α-dihydroxyprogesterone (DHP) and their 6α-methyl, 6β-methyl, 6α-fluoro and 6β-fluoro analogues were assayed for parenteral and oral progestational activity. P-DHP and A-DHP are equal in parenteral activity, each being about twice as potent as progesterone. P-DHP is strongly active orally, being 1 to 2 times as active as nore-thisterone, whereas A-DHP has only weak oral activity. Parenteral activity of P-DHP or A-DHP was not altered by 6-methylation. Oral activity of 6β-methyl-P-DHP was similar to P-DHP but both 6α and 6β-methyl-A-DHP were more potent orally than A-DHP. 6α fluorination had little or no enhancing effect on either parent compound when parenterally administered but did reduce oral potency. 6β fluorination made both parent steroids inactive by either route of administration. P-DHP and A-DHP have longer duration of activity than progesterone, moderate progestational effects still being present 25 days and 20 days, respectively, following a single 10 mg intramuscular injection. P-DHP is devoid of inherent androgenic, anti-androgenic, estrogenic, anti-DCA or corticoid activities.

COMPARISON OF ANTI-GRANULOMA, THYMOLYTIC AND GLUCOCORTICOID ACTIVITIES OF ANTI-INFLAMMATORY STEROIDS.

Summary A series of 15 corticoids was assayed for anti-granuloma, thymolytic and liver glycogen deposition activities in adrenalectomized male rats. The order of relative potency for the majority of the steroids was similar in the three bioassays. Exceptions were 6α-chloro-9α-fluoro-16α-hydroxyprednisolone acetonide acetate and 6α-fluoro-16α-methylprednisolone which had greater relative potencies in the anti-granuloma and thymolytic assays, and 9α-fluoro-16α-hydroxyprednisolone acetonide which had a greater relative potency in the liver glycogen deposition assay.

Adrenal adenine nucleotide-metabolizing enzymes: alterations induced by ACTH treatment.

The treatment of mice with ACTH caused an increase in adrenal 5′-nucleotidase activity. This increase appeared to be related to dose. Another phosphatase, ATPase, was not affected by ACTH. Cortisone administration resulted in a depression of adrenal ATPase activity apparently related to dose. Cortisone had no effect on adrenal 5′-nucleotidase activity. Properties of adrenal 5′-nucleotidase, such as intracellular distribution, substrate specificity, influence of pH, and Km, were investigated in normal as well as in ACTH-stimulated adrenals. An increase in 5′-nucleotidase activity occurred in the microsomal and soluble cytoplasmic fractions after ACTH. Treatment with ACTH did not alter substrate specificity, pH dependence, or velocity constant. The adrenals also contain an enzyme which is capable of converting cyclic 3′, 5′-AMP to 5′-AMP. The activity of this phosphodiesterase increases under ACTH stimulation. The intracellular distribution of this enzyme was studied. After treatment with ACTH, the activity increased only in the soluble cytoplasm fraction. The possibility is proposed that the sequential action of the cyclic 3′,5′-AMP phosphodiesterase and 5′-nucleotidase plays a role in the action of ACTH.

PHLORETIN, A WEAK ESTROGEN AND ESTROGEN ANTAGONIST.

Summary Phloretin is a very weak estrogen. It induces a uterotrophic effect in immature mice and in ovariectomized rats. Estradiol benzoate-induced uterine growth in the mouse and vaginal cornification in the castrate female rat are partially inhibited by concurrent treatment with large doses of phloretin. This compound is a weak inhibitor of pituitary gonadotrophins in parabiotic female rats and in intact immature male rats. Administration of phloretin to female rats on days 1–4 after mating decreased the number of pregnancies by 40%.

The effect of ACTH upon adrenal glucose-6-phosphate metabolizing enzymes☆

Abstract Haynes, Sutherland and Rall (1960) have proposed a mechanism of action of ACTH upon the adrenal gland in which G-6-P ∗∗ plays a most important role. ACTH was shown to activate adrenal phosphorylase, causing an increased production of G-1-P, and the subsequent conversion of G-1-P by phosphoglucomutase to G-6-P, results in an increased metabolism of G-6-P by oxidation to 6-phosphogluconic acid. This oxidation via the hexose monophosphate shunt produces TPNH and TPNH serves as a source of energy for various steps in the production of steroids ( Haynes and Berthet, 1957 ). However, G-6-P may also be metabolized by dephosphorylation, affected by the enzyme G-6-Ptase. Since we have been studying the effect of ACTH treatment upon certain adrenal enzymes ( Hilf et al., 1961 ), we felt that an investigation of the effects of ACTH upon G-6-Ptase might provide further insight into the metabolism of G-6-P. The activities of G-6-P dehydrogenase and 6-phosphogluconic dehydrogenase were also measured in ACTH stimulated adrenals. In this communication data are presented indicating that ACTH treatment caused a rapid decrease in G-6-Ptase activity.

Antigenicity of bovine cortical bone.

Summary Rabbits were immunized with finely ground, pulverized bovine cortical bone. It was demonstrated that the antibodies in the sera of these rabbits reacted with the bovine serum and the bovine red cell antigens present in the bone; however, after absorbing from these rabbit sera the bovine serum and bovine red cell antibodies, hemagglutination titers of low order still persisted. Grabar immunoelectrophoresis confirmed the results obtained by the hemagglutination assay and indicated the presence of 2 distinct antigens in bovine cortical bone unrelated to its serum and red cell content.

AUTOMATION OF THE LIVER GLYCOGEN DETERMINATION

The deposition of glycogen into the livers of adrenalectomized rats is a criterion used as an indication of glucocorticoid activity of ster0ids.l After the administration of the steroid to the animal, the animal is sacrificed, and the amount of glycogen in the liver determined. The increase in liver glycogen varies directly, within limits, with the amount of steroid administered. By comparing varied doses of a new synthetic corticosteroid with a standard corticosteroid, it is possible to determine the relative activity of the new steroid. The method for the determination of liver glycogen that had been in use in our laboratories for a number of years involves the isolation of glycogen by saponification of approximately 500 mg. of liver in hot 30 per cent KOH and then precipitation of the glycogen with 60 per cent ethanol. The amount of glycogen present was then determined, after suitable dilution with water, by the anthrone method of Seifter et d2 The initial dilution is estimated on the basis of the amount of the glycogen precipitate present, since the anthrone method is limited to a maximum of 60 pg. of glycogen. Visual estimation of this precipitate, even for a trained individual, has its shortcomings. In addition to the dilution problem, there was always the hazard of dust or lint causing a darker color with the anthrone reagent. Care must be taken to avoid this, and a great deal of time and effort is expended in this analysis. It was, therefore, deemed desirable to attempt to establish an autoanalytical method that could be routinely applied to the determination of rat liver glycogen. An automatic niodification of the liver glycogen method reported by Van der Vies? was adapted in our laboratory for use with the AutoAnalyzer. The method finally adopted and the results obtained with this method in comparison to the anthrone method are reported here.

Biological Activities of the 2-Acetofuran Derivative of 16α, 17α-Dihydroxyprogesterone:

Summary The 2-acetofuran derivative of 16α, 17α-dihydroxyprogesterone (AF) is 32–64 times as active a progestogen as progesterone (P) or the acetophenone derivative of 16α, 17α-dihydroxyprogesterone (D) when administered subcutaneously in the rabbit. AF is only 1/8–1/4 as active as norethisterone (N) and 1/8 as active as D when orally administered in this same assay. This progestogen has a long duration of activity in the rabbit when administered intramuscularly. A single injection of 5 or 10 mg produced an endometrial response which was still present 35 days later. Pregnancy is maintained in the ovariectomized rat by smaller doses of AF than that required for P and the concomitant administration of estrone enhanced this activity. This progestational steroid does not masculinize the rat fetus and is devoid of androgenic, estrogenic or glucocorticoid activities.

A new hypoglycemic compound 1-cyclohexyl-3-(5-indanylsulfonyl) urea

A new sulfonylurea compound,1-cyclohexyl-3-(5-indanylsulfonyl) urea (SQ 15,860) was hypoglycemic in rats, dogs and rabbits when orally administered. At lower doses this compound induced a greater depression in blood sugar in the rat than did tolbutamide. At higher doses SQ 15,860 induced a prolonged hypoglycemic effect without marked alteration in the extent of the decrease in blood glucose. In contrast, increasing the dose of tolbutamide did little to alter the duration of activity. The intraperitoneal LD50 for SQ 15,860 was 1580±60 mg./Kg., while that of tolbutamide was 850±42 mg./Kg. The oral LD50 for SQ 15,860 was greater than 8000 mg/Kg. and that of tolbutamide was 2046±219 mg./Kg.