Gordon W. Duncan

Antifertility Activities of Two Diphenyl-Dihydronaphthalene Derivatives

Summary U-10520A and U-11100A, derivatives of 1,2-diphenyl-3,4-dihydronaphthalene, possess oral antifertility activity in rats, guinea pigs, and rabbits. Efficacy, following daily doses as low as 5 μg, is restricted to first 4 days of pregnancy. Antifertility activity has not been observed in hamsters. These compounds cause minimal uterotropic stimulation and also inhibit estradiol-induced uterine weight increases. Gonadotropin inhibiting activity is not observed at therapeutic doses. In contrast to many compounds reported to effectively inhibit pregnancy, both U-10520A and U-11100A possess very favorable therapeutic ratios.

An Orally Effective Mammalian Antifertility Agent

Summary U-11555A, a derivative of 2,3-diphenylindene, is an orally active antifertility agent in laboratory mammals. In rats, its efficacy is limited to the period of tubal transport of the zygote. Single oral doses, administered any time within 4 days of breeding, effectively inhibit pregnancy. After the zygote has reached the uterus U-11555A is ineffective as a pregnancy inhibitor. At effective antifertility dosages, U-11555A does not exhibit significant progestational, antiprogestational, antigonadotropic, androgenic, or estrogenic activities. U-11555A inhibits the uterine and vaginal response to endogenous and exogenous estrogens.

Inhibition of prostaglandin F 2a or LH induced luteolysis in the pseudopregnant rabbit by 17 -estradiol.

Summary Administration of prostaglandin F2α (PGF2α) or luteinizing hormone (LH) induces luteolysis in the rabbit. The present study was designed to compare the effect of estrogen treatment on the luteolytic action of PGF2α and LH in pseudopregnant Dutch Belted rabbits. PGF2α (500 μg administered subcutaneously twice a day on days 9 through 12 of pseudopregnancy) reduced (p < .001) corpora lutea weights by day 14 and lowered peripheral plasma progestin levels on days 11 (p < .001) and 14 (p < .05). LH (50 μg intravenously on day 9) comparably reduced corpora lutea weights although plasma progestin levels increased due to LH-induced ovulations. In animals receiving 17β-estradiol (20 μg/day subcutaneously on days 9 through 12) plus LH, corpora lutea weights did not differ significantly from controls. Corpora lutea in rabbits receiving 17β-estradiol plus PGF2α were heavier (p < .05) than in animals receiving PGF2α alone but less (p < .05) than controls. This luteo-tropic effect of estradiol was also reflected by the presence of significant (p < .05) plasma progestin concentrations on days 11 and 14. A 5-fold increase in the dose of PGF2α did not completely overcome the luteotropic effect of 17β-estradiol.

Reproductive Mechanisms Influenced by a Diazocine

Summary 2,8-Dichloro-6,12-diphenyl-dibenzo[b,f][l,5] diazocine completely inhibited pregnancy when administered either orally or subcutaneously to female rats at doses as low as 0.5 mg daily for 7 days at time of mating. At higher doses, single treatments prior to completion of implantation were equally effective. Systemic or fetal toxicity did not occur at therapeutic doses. This compound also induced uterine growth, vaginal cornification, blastocyst implantation and inhibited gonadotropin activity. Each of these latter effects are indicative of estrogenic properties, and are probably involved with antifertility efficacy. This non-steroidal compound is a structurally unique addition to those agents with these biological activities.

Toxicologic and interrelated studies with an oxazolidinethione contraceptive

Abstract 5-(α,α,α-Trifluoro- m -tolyoxymethyl)-2-oxazolidinethione, or U-11,634, effectively inhibits pregnancy in rats at multiple oral or subcutaneous doses of 2.5 mg or a single subcutaneous dose of 5 mg. A toxicologic evaluation of this compound was performed at multiples of this therapeutic dose. The acute LD 50 studies were done intraperitoneally in the mouse (451 mg/kg) and orally in the rat (524 mg/kg). Significant signs of toxicity were not observed in swine photosensitization studies or in rat fetal studies. Rats tolerated an oral dose of 10 mg/kg/day for one month without significant untoward effect; however, higher levels (30 and 100 mg/kg/day) produced various effects, the most significant of which was an antithyroid effect. When U-11,634 was given orally to dogs for one month, it was slightly toxic at 30 mg/kg/day, moderately toxic at 100 mg/kg, and very toxic at 300 mg/kg/day. The signs of toxicity consisted of antithyroid effects in all the treated dogs, and toxic hepatitis in some of the dogs at the higher dosages. Additional studies in dogs and rats at 100 mg/kg/day indicated that the antithyroid effects in both species, and elevated bromsulfalein retention and alkaline phosphatase values in dogs reversed following cessation of treatment. The increase in monocytes in the blood and the bone marrow changes need further study. The antifertility effects of U-11,634 in rats were evaluated in the presence of exogenous thyroxine and iodine. This supplemental treatment did not change the pregnancy-inhibiting activity of U-11,634 nor did it inhibit pregnancy in the absence of U-11,634. The effect on early pregnancy of subacute treatment with known antithyroid agents was assessed. No inhibition of pregnancy was observed following their administration from proestrus through day 6 of pregnancy. On the basis of these observations and available literature reports, it is concluded that the antithyroid effect of U-11,634 does not account for the compounds antifertility efficacy.

Effect of 7α-Methylation on Biological Activities of Norethindrone

Summary A very substantial increase of oral gonadotropin inhibiting (34 X), pregnancy inhibiting (10 X) and uterotropic (24 X) potencies was observed for 7α-meth-y1-17 α-ethynyl-19-nortestosterone (U-13851) compared to 17-ethynyl-19-nortestosterone (norethindrone) even though progestational potency was not enhanced. Although anabolic and androgenic properties are greatly increased in some 7α-methyl derivatives of testosterone and 19-nortestosterone, U-13851 did not appear to produce a typical androgenic response in laboratory tests. The authors wish to express their appreciation to J. I. Northam for statistical analysis of data and to J. C. Cornette and A. D. Forbes for technical assistance.