Design, synthesis and bioassays of antagonists of LHRH which have high antiovulatory activity and release negligible histamine

Ljungqvist, Anders; Feng, Da Hsuan; Tang, Pui-Fun Louisa; Kubota, Minoru; Okamoto, Tadashi; Zhang, Yawen; Bowers, Cyril Y.; Hook, W. Alexander Van; Folkers, Karl

doi:10.1016/0006-291x(87)90953-3

Cited by 68 publications

(27 citation statements)

References 9 publications

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“…We have synthesized and bioassayed antagonists of luteinizing hormone-releasing hormone (LHRH) with high potency and diminished activity to release histamine (1). Our designs featured N6-nicotinoyl-D-lysine [D-Lys(Nic)] in position 6 and NE-isopropyllysine [Lys(iPr)] in position 8.…”

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confidence: 99%

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Antide and related antagonists of luteinizing hormone release with long action and oral activity.

Ljungqvist

Feng

Hook

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Antide is the decapeptide N-Ac-D-Nal(2),DPhe(pCl),D-Pal(3),Ser,Lys(Nic),D-Lys(Nic),LeuLys(iPr),Pro, D-Ala-NH2 [Nal(2) represents 3-(2-naphthyl)alanine; Phe(p-Cl) represents 3-(4-chlorophenyl)alanine; Pal(3) represents 3-(3-pyridyl)alanine; Lys(Nic) represents Ne-nicotinoyllysine; Lys-(iPr) represents N6-isopropyllysine], which is an antagonist of luteinizing hormone-releasing hormone (LHRH), which has high antiovulatory activity, releases negligible histamine, and is scheduled for scale-up, safety testing, and evaluation in the experimental primate and in clinical medicine. Thirty-five more peptides were synthesized, designed on antide with variations in positions 5-8. Antide showed oral antiovulatory activity at 600 pg (73%) and at 1200 pg (100%) with negligible difference between water and corn oil oral formulations.We have synthesized and bioassayed antagonists of luteinizing hormone-releasing hormone (LHRH) with high potency and diminished activity to release histamine (1). Our designs featured N6-nicotinoyl-D-lysine [D-Lys(Nic)] in position 6 and NE-isopropyllysine [Lys(iPr)] in position 8. We avoided the basic D-Arg6, which, in combination with Arg8 and a cluster of hydrophobic aromatic amino acid residues at the N terminus, has been implicated in the release of histamine (2-4). Herein are results from analogs with acylated aminocyclohexylalanine residues in position 6, from analogs in which Leu' has been substituted with other neutral residues, from a comparison of Lys(iPr)8 vs. N8-isopropylornithine at position 8 [Orn(iPr)8], and from tests on oral activity and duration of activity, oral and s.c. MATERIALS AND METHODSSynthesis. The peptides were synthesized by the solidphase method (1, 11).Purification. The peptides were purified by silica gel chromatography with the solvent system 1-butanol/acetic acid/water, 4:1:2 (vol/vol), or 4:1:5 (vol/vol), upper phase followed by gel filtration on Sephadex G-25. Alternatively, purification was achieved by gel filtration on Sephadex G-25 followed by chromatography on Sephadex LH-20 with the solvent system water/1-butanol/acetic acid/methanol, 90: 10:10:8 (vol/vol).The purity was checked by HPLC, TLC, and amino acid analysis. HPLC was performed on a Waters Associates instrument equipped with a model 660 solvent programer and either a uBondapak C18 or a Vydac C18 analytical column. Single peaks were obtained at flow rates of 2 or 1.5 ml/min using linear gradients of increasing acetonitrile in 0.01 M KH2PO4 (pH 3).

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“…Other reductions of anaphylactoid activity include increasing the distance between the positive charges in positions 6 and 8 by Args and a neutral residue in position 6 From our 52 peptides (1), 2 were chosen as models for further design.…”

mentioning

confidence: 99%

Antide and related antagonists of luteinizing hormone release with long action and oral activity.

Ljungqvist

Feng

Hook

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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“…All four analogues are short acting. A similar set of derivatives (7-10) was significantly less potent in vitro, likely due to increased steric hindrance (7,8) and charge distribution (9, 10). Interestingly, 9 (with intermediate duration of action) showed some extended duration of action over 10 (with short duration of action).…”

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confidence: 99%

Iterative Approach to the Discovery of Novel Degarelix Analogues: Substitutions at Positions 3, 7, and 8. Part II

et al. 2005

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Degarelix, (FE200486, Ac-D-2Nal 1 -D-4Cpa 2 -D-3Pal 3 -Ser 4 -4Aph(L-Hor) 5 -D-4Aph(Cbm) 6 -Leu 7 -Ilys 8 -Pro 9 -D-Ala 10 -NH 2 ) is a potent and very long acting antagonist of gonadotropin-releasing hormone (GnRH) after subcutaneous administration in mammals including humans. Analogues of degarelix were synthesized, characterized and screened for the antagonism of GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. The duration of action was also determined in the castrated male rat assay in order to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone (LH) release. Structurally, this series of analogues has novel substitutions at positions 3, 7, 8 and N α -methylation at positions 6, 7 and 8 in the structure of degarelix. These substitutions were designed to probe the spatial limitations of the receptors cavity and to map the steric and ionic boundaries. Some functional groups were introduced that were hypothesized to influence the phamacokinetic properties of the analogues like bioavailability, solubility, intra-or inter-molecular hydrogen bond forming capacity and ability to bind carrier proteins. (18) had a longer duration of action {inhibited LH (>96 h) release} than azaline B, however they were shorter acting than degarelix. Hydrophilicity of these analogues, a potential measure of their ability to be formulated for sustained release, was determined using RP-HPLC at neutral pH yielding analogues with shorter as well as longer retention times. No correlation was found between retention times, antagonist potency or duration of action.

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“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org phylaxis secondary to histamine release from the combination of the hydrophobic N terminus and basic/hydrophilic C terminus (Ljungqvist et al, 1987;Flouret et al, 1992). Thirdgeneration GnRH-ant (cetrorelix and ganirelix) have amino acid substitutions in these and other positions and do not induce histamine release (Table 1).…”

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The Evolution of in Vitro Fertilization: Integration of Pharmacology, Technology, and Clinical Care

Feinberg

Bromer

Catherino

2005

J Pharmacol Exp Ther

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For the couple having trouble achieving pregnancy, the options and opportunities for assistance have never been brighter. Options such as controlled ovarian hyperstimulation, in vitro fertilization, and intracytoplasmic sperm injection have been developed over the past five decades and provide hope for couples that previously would have been considered infertile. In vitro fertilization and intracytoplasmic sperm injection represent a coalescence of advances in physiology, endocrinology, pharmacology, technology, and clinical care. In vitro fertilization has assisted well over one million couples in their efforts to start or build a family, and the demand for such services continues to increase. The purpose of this manuscript is to review the pharmacological advances that made controlled ovarian hyperstimulation, and therefore in vitro fertilization and intracytoplasmic sperm injection, possible. We will discuss the early stages of gonadotropin use to stimulate ovarian production of multiple mature eggs, the advances in recombinant technology that allowed purified hormone for therapy, and the use of other hormones to regulate the menstrual cycle such that the likelihood of successful oocyte retrieval and embryo implantation is optimized. Finally, we will review current areas that require particular attention if we are to provide more opportunity for infertile couples.Controlled ovarian hyperstimulation (COH), in vitro fertilization (IVF), and intracytoplasmic sperm injection have become the standard of care for many couples with infertility. The combination of pharmacologic and surgical manipulation of the menstrual cycle is the key to improving pregnancy rates. The history and evolution of COH, IVF, and intracytoplasmic sperm injection has been rapidly developing and continues to change at an ever increasing pace (Fig. 1). As we learn more about the molecular basis of cellular communication and signaling, pharmacologic treatments with greater efficacy can be developed. Improvements in embryo culture techniques and embryo cryopreservation will similarly enhance outcomes. The purpose of this review is to summarize the history and development of the pharmacology that has made COH and IVF successful.In a typical menstrual cycle, there is the formation of a single dominant follicle, from which ovulation of a single oocyte occurs each month. For the fertile couple, this menstrual cycle has a 20% chance of resulting in a pregnancy; however, for infertile couples, the chance of pregnancy with one oocyte can be well under 5% per cycle. Over the past 50 years, pharmacologic agents have been developed to increase the likelihood of pregnancy by increasing the number of eggs released and available for fertilization.To clarify the obstacles to fertility that have been overcome as well as the challenges that remain, we will review the physiology of the menstrual cycle, major historical developments, and the therapeutic evolution and current use of medications used during controlled ovarian hyperstimulation and in vitro...

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Design, synthesis and bioassays of antagonists of LHRH which have high antiovulatory activity and release negligible histamine

Cited by 68 publications

References 9 publications

Antide and related antagonists of luteinizing hormone release with long action and oral activity.

Antide and related antagonists of luteinizing hormone release with long action and oral activity.

Iterative Approach to the Discovery of Novel Degarelix Analogues: Substitutions at Positions 3, 7, and 8. Part II

The Evolution of in Vitro Fertilization: Integration of Pharmacology, Technology, and Clinical Care

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