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J Strecke

Publications and source records attributed to J Strecke.

At least 19 recordsLinked to original sources
PubMed1987

Quantitative structure-activity relationships of estrogenic steroids substituted at C14, C15.

The uterotropic activity of thirty 3-methoxyestradiol derivatives is measured and discussed on the basis of X-ray crystallographic results and quantitative structure-activity relationship analyses involving hydrophobic substituent constants pi and f as well as steric parameters Pr and L. In addition, estrogenicity is compared to data of interceptive activity and receptor binding affinity. All the biological data exhibit a high degree of intercorrelation. 17 beta-Hydroxysteroids having 14 alpha configuration reveal a generally better capability of high-affinity binding than those being 14 beta configurated. Between the uterotropic activity and the hydrophobicity of C14, C15 substituents, statistically significant correlations are found which suggest a close contact between the steroidal D-ring subsite and the receptor protein (e.g. for 14 alpha steroids: log UDD = -0.996 pi -0.392; n = 9, r = -0.943, s = 0.235, t = -7.5, alpha less than 0.001). The hydrophobic nature of both 14 alpha and 14 beta medium-sized substituents employed is shown by QSAR regressions to exert a stronger influence than steric effects. Furthermore, there are indications to additional hydrogen bonding and steric repulsion phenomena. As to the receptor-binding models discussed in the literature, it is concluded that the receptor protein has a high conformational flexibility to accommodate very different drug structures all having the common phenolic ring A. But, if an appropriate spacing of steroidal key atoms is recognized by the receptor and, consequently, the steroid-receptor complex is formed, the binding is complemented by hydrophobic interactions also in the D-ring region.

Animals↗
PubMed1985

[Chromosome analysis of female baboons following treatment with STS 557 and levonorgestrel].

Adult, female baboons (Papio hamadryas) were administered orally once 18 h p.c., either 1.6 mg STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4;9(10)-dien-3-one) or 1.6 mg levonorgestrel. Investigations of the bone-marrow cells of these animals showed, compared to untreated controls, no signs of increased chromosome aberrations caused by the substances. The relative frequency of chromosome aberrations were estimated for controls: STS 557: levonorgestrel with 0.60 +/- 0.35 : 0.55 +/- 0.39 : 0.92 +/- 0.46%, respectively. The differences between the three groups investigated in the exact Fisher-test (2 alpha = 0.05) were not significant.

Animals↗
PubMed1983

Interceptive activities of STS 557 in rabbits, mice and rats.

STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) is a interceptive agent in rabbits, mice and rats. In rats, it also shows post-implantational pregnancyterminating activity. In rabbits treated orally before mating or after ovulation for three consecutive days, it inhibited pregnancy largely at total doses of 0.08 mg/kg in the former and completely with 8.0 mg/kg in the latter case. A single subcutaneous dose of 40 mg/kg given on day 1 of pregnancy inhibited completely nidation in rats. In inhibition of pregnancy in rats could also be realized when the dose of 40 mg/kg was distributed on several days and given subcutaneously at daily doses of 5.0 mg/kg on days 1--8 of pregnancy, and even only daily doses of 2 mg STS 557/kg were needed in this respect, if animals which showed no living conceptuses were scored as "non-pregnant". STS 557 was effective in terminating pregnancy in rats, too, when given subcutaneously after implantation for 4 days at daily doses of 50 mg/kg, beginning on day 5 or on day 8 of pregnancy. The nidation inhibiting effects of STS 557 in rabbits treated pre-coitally, and in mice as well as in rats treated post-coitally were more marked than those of levonorgestrel. The interceptive and post-implantational inhibiting activity of STS 557 may be based on its antiprogestagenic properties. Luteolysis in the nidation phase can be excluded as shown by radioimmunoassay of progesterone in rats. The antigestagenic effects on the endometrium in rats were evident in the diamine oxidase assay. The acceleration of tubal egg transport, the morphological changes of the endometrium shown by scanning electron microscopy, and the effects on blastocyst transfer, all investigated in rats, suggest peripheral mechanisms of action.

Amine Oxidase (Copper-Containing)↗
PubMed1983

Long term toxicological studies on the progestin STS 557.

The toxicity of 17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one (STS 557) was studied by its oral administration of 0.1, 1.0 or 10.0 mg/kg/day to Wistar rats for six months, and of 0.01, 0.1 or 1.0 mg/kg/day to beagle dogs for six months, respectively. Levonorgestrel at a dose of 1.0 mg/kg/day was used as the standard in the dog study. With respect to the progestational activity of the compound the main target organs were the hypophysis, the reproductive organs and the adrenals. Mammary hyperplasia was observed in dogs treated with STS 557 or levonorgestrel at the dose of 1.0 mg/kg/day, but in no case mammary nodules could be detected. At the dose of 1.0 mg/kg/day STS 557 and levonorgestrel were found to increase the plasma insulin response to i.v. glucose in bitches, but neither the mean blood glucose levels nor the glucose utilization were affected. Moreover, during administration of both steroids to dogs temporary changes in serum concentrations of triglycerides and total cholesterol were noted. The results obtained in rats and dogs from functional and morphological investigations did not reveal any toxic side effects of STS 557 on the liver, the kidneys, the bone marrow or on blood coagulation. The effects on the reproductive organs observed following STS 557 especially in dogs are related to both the hormonal effects of the compound and the specific response of the dog to potent progestagens.

Animals↗
PubMed1982

Further report on the endocrinological profile of 17 alpha-cyanomethyl-17 beta-hydroxy-estra-4,9(10)-diene-3-one (STS 557) in rodents.

STS 557, a new orally active progestin with antifertility properties has been tested for uterotrophic, antiuterotrophic, vaginotrophic, and antiovulatory effects. Further, maintenance of pregnancy in ovariectomized mice, influence on pregnancy in mice and rats, and conditioning of the immature rat uterus for decidual response were investigated. Both estrogenic and anti-estrogenic activities in mice and rats were found to be very low. STS 557 fails to maintain pregnancy in ovariectomized animals but does not interfere with pregnancy in intact mice if implantation already took place. Moreover, no effects have been found regarding the influence on the first ovulation in prepuberal rats. The biological profile of STS 557 in animals seems to make this compound suitable for use as a post-coital contraceptive.

Animals↗
PubMed1981

[Chromosomal analysis of baboons and their mothers, following application to mothers of potentially post-ovulation fertility-inhibiting steroids (author's transl)].

One single does of 0.4 mg of steroid compounds Levonorgestrel (13-ethyl-17alpha-ethinyl-17beta-hydroxy-gon-4-en-3-on) or STS 557 (17alpha-cyanomethyl-17beta-hydroxy-13beta-methylgona-4.9-dien-3-on) was administered to each of six baboon mothers, right after mating. No indication whatsoever to possible mutagenic action of the compounds applied under the given experimental conditions were recordable from the bone-marrow cells of the mothers nor from the lymphocytes of peripheral blood of their newborns. Chromosomal aberrations recorded from this species were within normal limits.

Animals↗
PubMed1980

Embryotoxic effects of post-coital fertility inhibiting steroids.

In mice post-coital estrogens caused retardation of tubal egg cleavage, whereas post-coital progestins stimulated egg division. In rats the situation was reversed. In this species estrogens accelerated the tubal embryo development and vice versa; the progestin STS 557 arrested division of embryos resting in the tube. Normal implantation occured following transfer of early blastocysts from estrogen-treated mice to untreated mice, but not following transfer of blastocysts from untreated animals to estrogen-treated animals. This shows that post-coital estrogens do not affect the embryos directly but they disturb the physiological integrity of the endometrium required for proper implantation.

Abnormalities, Drug-Induced↗
PubMed1980

STS 557 as an interceptive in rodents and baboons.

Studies with mice, rats, guinea pigs and baboons were undertaken to define the interceptive action of the new progestin STS 557 (17 alpha -cyanomethyl-17 beta-hydroxy-estra-4.9(10)-diene-3-one) and to compare it with other progestins used in oral contraceptives. STS 557, norethindrone and norethindrone acetate reduced deciduoma formation as well as the number of implantations in mice and rats. Chlormadinone acetate and levonorgestrel when administered at the appropriate dose could not prevent early pregnancy or deciduoma formation. But in contrast to STS 557, levonorgestrel maintained early pregnancy in ovariectomized rats. On the other hand, STS 557 was ineffective as a postcoital agent in guinea pigs. When 0.4 mg STS 557 was orally administered to 37 female baboons 3 or 6 h after the mating period, only one pregnancy occurred in a total of 60 cycles investigated (controls: 11 pregnancies in 12 cycles investigated). The results are discussed in view of the development of an interceptive method based on STS 557.

Animals↗
PubMed1980

[Comparative study of the estrogenic, antifertility and antigonadotropic effects of modified estrogens].

Estrogen (in uterotropic test on sexually immature female rats), antifertile (in experiments on sexually mature pregnant female rats), and antigonadotropic (in a test on sexually immature male rats) properties of some 2- and 4-bromine and silylsubstituted estradiols were compared in oral administration. 4-silylestradiols expressed marked antigonadotropic effects equal by activity to mestranol standard, and reduced as compared with the standard antifertile and estrogenic properties. 2- and 4-bromide and 2-silylestradiols were weakly active or inactive oral estrogens and possessed no antifertile properties.

Animals↗
PubMed1979

Morphometric investigations on endocrine glands. V. Changes in the testes of Wistar rats after application of chlormadinone acetate and norethisterone acetate.

In growth inhibiting tests of rat testes the tubular diameter and, somewhat less sensitive, the nuclear volume of the Leydig cell follow the weight changes. Chlormadinone acetate shows antigonadotropic activity only at high doses and a dose-dependent antiandrogenic activity. The dose-weight curve under norethisterone acetate has a minimum at 4.2 mg/rat/14 days; higher doses seem to be accompanied by androgenic efficiency.

Animals↗
PubMed1978

[Postcoital contraception in primates. II. Examination of STS 153 and STS 287 as interceptives in the baboon (Papio hamadryas)].

The interceptive activity of 2 new synthesized steroid compounds: STS 153 (17 beta-Phenylaminocarbonyloxy-estra-1,3,5(10)-triene-3-methyl ether and STS 287 (16 alpha-Bromo-17 beta-[N',N'-dimethylhydrazino]-carbonyloxy-estra-1,3,5(10)-triene-3-methyl ether) and of 17 alpha-Ethynylestradiol was investigated in baboons.--Postcoital oral administration of 1--3 mg/kg b. w. STS 153 for 5--7 days and of 1 mg/kg b. w. STS 287 for 5 days resulted in a fertility inhibition of about 90% and 95% respectively. A dose of 2 mg/kg b. w. of ethynylestradiol was necessary to attain complete fertility inhibition. Following administration of STS 153 and STS 287, side effects were not observed. Pharmacokinetic aspects are discussed.

Animals↗
PubMed1978

Relationship between uterotrophic and interceptive activities of steroidal estrogens.

The steroidal estrogens ethinylestradiol, mestranol and the synthetic "impeded" estrogen derivatives STS 456, STS 593 and J 628 were studied for their postcoital antifertility activity and estrogenicity in mice, rats and rabbits. Results of these studies suggest a positive relationship between these two biological endpoints with the exception of the findings in rats. As seen in uterotrophic--anti-implantation ratio, in view of only one species it is possible to dissociate the interceptive and the unwanted uterotrophic activities. The profound species differences in the effects of exogenous estrogens on the nidation phase are discussed.

Animals↗
PubMed1978

[Postcoital contraception in primates. I. Action mechanism of a potential postovulatory fertility-inhibiting substance STS 456 in the baboon (Papio hamadryas)].

With the substance STS 456, an estrogenic active steroid, a high fertility inhibition could be obtained in the pavian, when administered p. o. over a 5 day period postcoital. The effectiveness and also the side effects were dose dependent. The antifertility mechanism is based on an luteolytic effect, demonstrated by analytical hormonal investigations. The inhibition of the synthesis of steroids in the ovary affected not only progesterone but also the estrogens.

Animals↗
PubMed1978

Influence of 3-methylether of ethinylestradiol (Mestranol) on oviductal egg transport in rats.

The development of fertilized eggs and their transport through the oviduct were studied in rats treated orally with 3-methylether of ethinylestradiol (mestranol) at a single administration in different doses. The ED50 values were in the same range (0.11--0.34 mg mestranol/kg b.w.) as well in postcoital pregnancy inhibition test as in the experiments on tubal egg contents on day 3 as in implantation sites in niagara blue test on day 6. This suggests that the uniform cause of pregnancy inhibition of postcoital mestranol treatment on day 1 in rats is the acceleration of tubal egg transport. The ED50 of mestranol given on day 1 shortened the stay of eggs in tubes to 24 hours. Mestranol dosage above the ED50 reduced the tubal stay towards two days in comparison to five days in control animals. The number of eggs prematurely expelled from the tubes into the uterus was relatively high on day 2 and 3 in animals treated with mestranol in high dosage and with ligated cervix, compared with animals without ligation. But on day 4 on blastocysts were found. This result shows that the prevention of pregnancy is caused by the expulsion of blastocysts from uterus and/or the degeneration of zygotes in utero. Blastocysts or morulae recovered from treated rats in high dosage were transferred to the uteri of pseudopregnant recipients: 29% developed into normal term foetuses compared to 29 or 30% for both untreated control groups.

Animals↗