HERBAL CONTRACEPTIVES: EVALUATION OF ANTIFERTILITY POTENTIAL OF HIBISCUS ROSA‑SINENSIS (LINN.)

This review explores, evaluates, and analyzes the contraceptive potential of Hibiscus rosa-sinensis L. There are large numbers of synthetic contraceptives available in the market. These synthetic contraceptives are associated with many side effects ranging from user discomfort to toxicity. India is a land of traditional herbal medicines. People are finding and exploring the advantages associated with herbal contraceptives because of their lower side effects. Herbal contraceptives have lower cost of development as compared to modern medicine. This review explores the recent advances in development that offers many benefits for shifting the paradigm for herbal contraceptives. From times immemorial, references have been made for the plants that possess antifertility properties. This review explores the need for the development of herbal contraceptives from the plant H. rosa-sinensis L. H. rosa-sinensis L is reported to have antiovulatory activity. However, the need of the hour is to assess and carry out toxicological studies and initiate development activity for formulation development.

Antagonists of LHRH with Histidine in the Priority Position 8

Sixteen new designs of antagonists of the luteinizing hormone releasing hormone (LHRH) with histidine in position 8 were synthesized, because this position is critical both for antiovulatory activity and the side effect of histamine release. The most potent antagonist was NAcDQal-DpClPhe–D 3 Pal– Ser–cPzACAla–DPicLys– Leu– His – Pro –DAlaNH2, which showed 33% AOA at 0.25 μg. The histamine release was remarkably negligible by an ED50 of 308 μg/ml which is superior to 186 μg/ml for LHRH and comparable to 300 for Antide.The relative basicities of His, Arg, and ILys in position 8 of antagonists appear to influence both the level of potency of AOA and a negligible to a significant release of histamine. The least basic His8-analogs can have the lowest AOA and the highest ED50. The very basic Arg8-analogs can have the highest AOA and the lowest ED50. The moderately basic ILys8-analogs can be a compromise for acceptable levels of potency and safety.

Design, Synthesis and Biological Evaluation of Antagonists of LHRH by Criteria of Potency, Safety and Solubility

Some analogs of Antide and congeners with higher water solubility have been synthesized by substitutions in positions 1, 5 or 6 with hydrophilic residues. In position 1, D-3-Qal has been incorporated in four peptides and D-3-Pal in one peptide. In positions 5 and 6, D and L-3-Pal, PzAla and (DSer)Lys have been tried. In one peptide, D—(AcDSer)Lys was substituted in position 6.Most of the new analogs had lower AOA (antiovulatory activity) than the parent compounds but three potent analogs were identified. The first one, [N — Ac— D — 3-Qal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D — PicLys6,ILys8,D — Ala10]— LHRH, had 55% AOA at 0.25 μg and 100% at 0.5 μg. Its ED50 for in vitro histamine release was 171 ± 17 μg/ml which is an increase from 49±4.8 μg/ml for the parent compound with N—Ac-D-2-Nal [1].The second analog, [N — Ac— D — 2-Nal1,DpClPhe2,D — 3-Pal3,PicLys5,D — (DSer)Lys6,ILys8,D—Ala10] — LHRH, had 69% AOA at 0.25 μg and 95% at 0.5 μg. This analog released somewhat more histamine than the parent analog featuring D-PicLys6, the ED50 being 18 μg/ml compared to 93 ± 11 for the parent analog.The third analog is:[N — Ac— D— 2-Nal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D—PzAla6,ILys8,DAla1]— LHRH. The AOA for this analog was 63% at 0.25 μg and the ED50 for histamine release 88±6.4 μg/ml.

Position 10 is Critical for Antagonists of the Luteinizing Hormone-Releasing Hormone and for Inhibition of Ovulation in Rats

Eleven analogs of the luteinizing hormone-releasing hormone (LHRH) have been designed, synthesized, bioassayed and compared for antiovulatory activity (AOA) in rats. The emphasis of design was on analogs with D–Ala10, Sar10, D–Ser10, (desGly10, NHEt), D–Abu10, Gly10, and with substitutions in position 5, 6, and 8.High antiovulatory activity was obtained with analogs having D– Ala in position 10. Four earlier analogs, 1, 4, 11 and 13, with D– Ala in position 10, showed 67-100% AOA at 0.25 μg in rats. Analog 1 showed 60% AOA at 0.125 μg. The replacement of D–Ala10 in analog 11 by Sar10 in analog 12, retained activity, 62% vs. 67% AOA at 0.25μg, 100% vs. 90% AOA at 0.5 μg. This analog with Sar10 was the only one that did not show substantial loss of activity upon replacement of D–Ala10.

Relative Potencies of Antagonists of the Luteinizing Hormone Releasing Hormone with Lys8 and Arg8 and Substitutions in Positions 3 ,5 ,6 ,7 and 8

Antagonists of the luteinizing hormone releasing hormone (LHRH) of increased potency is a goal for control of ovulation. In the design and synthesis of 26 decapeptides, emphasis was given to analogs with Lys8 and Arg8 and with various substitutions in positions 3, 5, 6, 7 and 8. Two antagonists, [N-Ac-ᴅ-2-Nal1,ᴅ-pClPhe2,ᴅ-3-Pal3,Ser4,Tyr5,ᴅ-Arg6,Leu7,Lys8,Pro9,ᴅ-Ala10] - NH2 and [N-Ac-ᴅ-2-Nal1.ᴅ-pClPhe2,ᴅ-3-Pal3,Ser4,Arg5,ᴅ-3-Pal6,Leu7,Arg8,Pro9,ᴅ-Ala10]-NH2 showed 80-85% antiovulatory activity (AOA) at 0.25 μg in the rat. The latter antagonist showed 60% AOA at 0.125 μg. Of four pairs of analogs with Arg8 and Lys8, respectively, two pairs favored Lys8 over Arg8 for potency. One pair showed negligible difference and another pair favored Arg8 over Lys8. There is specificity of substitution for potency. In other antagonists, ᴅ-3- Pal3, Tyr5 or Phe5, ᴅ-Arg6 and Leu7 or Nle7 or Val7 and Arg8 were variously effective substitutions for increase of potency and reduction of histamine release.

Antagonists of the Luteinizing Hormone Releasing Hormone with Emphasis on Amino Acids in Position Five

Seventeen analogs of the luteinizing hormone releasing hormone (LHRH) have been synthesized, bioassayed, and compared for antiovulatory activity (AOA) in rats. The emphasis of design was replacement of Tyr5 of LHRH. Position 5 has not been extensively studied. [N-Ac-D-2-Nal1 , D-pClPhe2 , D-3-Pal3 , D-Arg6 , D-Ala10 ]-LHRH was the baseline for new designs. Comparison of the AOA's of the 17 analogs with the baseline revealed the two peptides with Phe5 and 3-Pal5 had equivalent AOA's, and were the best of the 17, and about 45% more potent than the baseline. Analogs with pClPhe5 , oClPhe5 , α-MepClPhe5 , 2-Nal5 , Trp5 , and His5 were less potent than the Phe5 -and 3-Pal5 -analogs. Based on the Phe5 -analog, eight other analogs were synthesized with changes in positions 1, 2, 3 and 7 and although none were better than the baseline, 5/8 showed 20-60% AOA's at 250 ng and revealed optimum positions for new designs.

Analogs of the Luteinizing Hormone Releasing Hormone having the Azagly10 Moiety with Antiovulatory Activity

Twenty-four new analogs of the luteinizing hormone releasing hormone (LHRH) were synthesized and bioassayed for antiovulatory activity in rats. [N-Ac-3⊿Pro1, pF-D-Phe2, D-Trp3,6, Azagly10]-LHRH com pletely inhibited ovulation at 6 μg and was the most potent of the 24, and is a relatively potent antagonist in the field. The Azagly- and Ac-NHNH- and D-Alamoieties in position 10, and D-Arg in position 6, and diverse substitutions in position 1 were emphasized. D-Arg6 was inferior to D-Trp6, and pCl-D-Phe6 appeared superior to D-Trp6. D-Trp3,6 was superior to D-2-Nal3,6 and D-His3,6.