Agonist (ovulation induction) and post-coital contraceptive properties of [D-Ala6] and [D-Trp6]-LHRH series.

Seven derivatives of LH-RH, representing the [D-Ala6] or [D-Trp6] series, with or without a Fujino modification, were evaluated for ovulation-inducing (agonist and post-coital contraceptive activity in rats. Six of these analogues had a high degree of agonist and pregnancy-terminating potency. In general, several modifications can result in a particular series of composite molecules that possess a biologic potency greater than each of its predecessors; this correlation of structure with activity was more consistent in the [D-Ala6]-series than in the [D-Trp6]-series. The relationship between structural modifications, resistance to enzyme degradation (based on literature reports) and increased biologic potency is discussed.

The anti-reproductive pharmacology of LH-RH and agonistic analogues.

LH-RH and three particular ("super") analogues were evaluated for agonistic (ovulation-induction and short-term uterotrophic properties) and postcoital contraceptive activity in rodents. Additionally, LH-RH and/or a representative analogue (D-Ala6-des Gly10-Pro9-LH-RH ethylamide) were tested for postcoital contraceptive/vaginal smear/return to fertility effects, precoital contraceptive activity, and effects on puberty in the immature female. All compounds induced ovulation and uterotrophic effects and terminated pregnancy when administered either pre- or post-implantation. LH-RH and the representative analogue, while terminating pregnancy postcoitally, produced an associated break in the characteristic leucocytic vaginal smear of pregnancy to one of cornification by day 12; at this time mating and insemination were reestablished and all rats carried to normal term. Precoitally, LH-RH administered to nembutalized (but not to unblocked) rats produced a 50% reduction in the pregnancy rate and a 38% decrease in the number of viable pups delivered. In immature rats, the representative analogue delayed puberty (i.e. vaginal canalization) and retarded the growth of the ovaries, uteri, and anterior pituitary gland. The collective data strongly support the concept that LH-RH and agonistic derivatives, in spite of their putative pro-fertility classification, are characteristically antifertility by nature. Since the latter effect appears to be the paradoxically dominant one, it is suggested that LH-RH agonism is synonymous with contraception. Furthermore, such peptides may represent a new potential approach to fertility control.

Postcoital contraceptive effects of agonist analogs of luteinizing hormone-releasing hormone.

Various analogs of synthetic hypothalamic luteinizing hormone-releasing hormone (LH-RH) were evaluated for agonistic (ovulation-inducing), postcoital contraceptive, and direct uterotrophic activities. All analogs showing agonistic activity also possessed the ability to terminate pregnancy, as did LH-RH; there appeared to be a direct relationship between agonistic and postcoital potency and activity. The highly potent and active LH-RH agonist, D-[Ala]6-des-[Gly]10-pro9-ethylamide-LH-RH, proved to be the most potent and active postcoital preimplantational and postimplantational antifertility agent. In contrast to LH-RH, none of the analogs tested in the hypophysectomized animal produced a uterotrophic effect, revealing a selective extrapituitary effect of the parent hormone. The collective data demonstrate that peptides derived from LH-RH and bearing agonistic properties can terminate pregnancy postcoitally, via disruption of the pituitary-ovarian reproductive complex. Possible mechanisms are discussed, and the use of members of this neurohormonal class as potential profertility agents should be weighed with caution.

Post-coital contraceptive effects of an agonistic analogue of luteinizing hormone releasing hormone.

An analogue of synthetic hypothalamic LRH, D-[ALA]6-DES-[GLY]10-PRO9-ethylamide-LRH (Wy-18,481) was evaluated for agonistic (in vivo LH-releasing and ovulation-inducing), post-coital contraceptive and reproductive target organ effects. Both LRH and the analogue terminated pregnancy; there appeared to be a direct relationship between agonistic and post-coital contraceptive potency and activity. The analogue proved to be a potent agonist and both a pre-and post-implantational post-coital anti-fertility agent. In contrast to LRH, the congener did not produce a uterotrophic effect in the hypophysectomized rat. The data suggest that agonist analogue(s) of LRH can terminate pregnancy via hyperstimulation of the pituitary-ovarian-reproductive complex and the use of members of this neurohormonal class as potential clinical pro-fertility agents should be weighted with caution.

PIP: Investigations with the compound D-(ALA)(6)-DES-(GLY)(10)-PRO(9)-ethylamide-LRH (Wy-18,481) as a luteinizing hormone-releasing hormone (LH-RH) agonist and as a postcoital contraceptive are described. Postcoital contraceptive studies included the use of rats and of rabbits, and in vivo evaluation of LH-RH agonism studied gonadotropin (LH)-releasing activity in ovariectomized, steroid blocked rats and ovulation induction in the rat. Uterotrophic activity was evaluated in intact, immature mice and in 25-day-old hypophysectomized rats. Both LH-RH and the analogue terminated pregnancy, and the analogue was proven to be a potent agonist and both a pre- and postimplantational postcoital antifertility agent. The congener failed to produce the uterotrophic effect in the hypophysectomized rat that LH-RH did. The mechanisms by which LH-RH and agonistic analogue terminate pregnancy are unclear. The data suggest that they can operate via hyperstimulation of the pituitary-ovarian-reproductive complex and should be used with caution when used as potential profertility agents.

Antagonism of luteinizing hormone release and of ovulation by an analog of the luteinizing hormone-releasing hormone.

Two varients of LH-RH, less than Glu-D-Phe-Trp-D-Ala-Leu-Arg-Pro-Gly-NH2 (I) and less than Glu-D-Phe-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-NHCH2CH3 (II), have been synthesized by solid-phase methods. Both peptides strongly inhibit the LH-RH induced secretion of LH in an in vitro assay; however, only I proved effective in preventing ovulation in the 4-day cycling rat.

Luteinizing hormone-releasing hormone. Antiovulatory activity of analogs substituted in positions 2 and 6.

Ten analogs of luteinizing hormone-releasing hormone (LH-RH) substituted in position 2 with D-amino acids and at 6 with either a D-amino acid or a nonasymmetric amino acid were synthesized by solid-phase methodology and assayed for antiovulatory activity. [D-Phe2]-LH-RH substituted in the 6 position with D-Ala, D-Leu, D-Arg, D-(Ph)Gly, D-Phe, or 2-Me-Ala possessed varying degrees of antiovulatory activity. [D-p-F-Phe2-D-Ala6]-LH-RH was one of the most active antiovulatory compounds, while the [D-p-Cl-Phe2-D-Ala6]-LH-RH analog was devoid of activity at a comparable dose.

The identification of some human metabolites of norgestrel, a new progestational agent.

PIP: Norgestrel 1 (racemic 13-beta-ethyl-17-alpha-hydroxygon-4-en-3-one) a progestational agent with an angular ethyl group between Rings C and D, was studied by mass spectrometry to discover its structural characteristics. Synthesis of postulated metabolites of Norgestrel 1 for use in identification is described and structural formulas are given. Urine was used as a source to characterize fractions via mass spectra, and the fraction spectra are listed. The major metabolite was 13-beta-ethyl-17-alpha-ethynl-5-beta-gonan-3-alpha-1m-beta-diol 8c.^ieng