Introduction ON JUNE 24, 1971, Andrew V. Schally announced the determination of the primary structure of porcine GnRH at The Endocrine Society Meeting in San Francisco. This announcement was followed by publications by Matsuo et al. (1, 2) and Baba et al. (3) on the proposed amino acid sequence for porcine GnRH and its synthesis and by Burgus et al. (4) who characterized ovine GnRH and found the sequence to be identical with that of porcine GnRH. The physiological and therapeutic importance attributed to the discovery of the new substance was greatly increased by the prospect of the design of potent and long acting GnRH agonists and antagonists. Since that time more than 2000 analogs of GnRH have been synthesized. The impact of research of GnRH and its analogs on clinical medicine recently led Ziporyn (5) to note, “There's almost no subspecialty of medicine that will be left untouched by the [research] advances associated with LHRH or its analogs.” It is the intent of this article to provide a historical ...

Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: rationale and perspective.

I. Introduction II. Amino Acid Sequences of GnRH Receptors A. GnRH receptor cDNAs B. General structural features C. Covalent modifications D. Gene structure III. Structure-Activity Relations of GnRH Peptides A. Overview B. Comparative structures and activities of vertebrate GnRHs C. Roles of individual amino acids in GnRH activity at the mammalian receptor D. Conclusions from peptide structure-activity data IV. Structure and Conformation of GnRH and Its Analogs A. Early studies of GnRH conformation B. Integrated computational and experimental studies C. Exploration of the entire conformation space of GnRH analogs V. Functional Structure of the Receptor and Ligand-Receptor Complex A. Extracellular domains B. Helix domains C. Intracellular loop domains D. Computational modeling of three-dimensional receptor structure VI. Conclusions

/pdf/molecular-mechanisms-of-ligand-interaction-with-the-53djy3r057.pdf

Molecular Mechanisms of Ligand Interaction with the Gonadotropin-Releasing Hormone Receptor

GnRH analogues—agonists and antagonists

To eliminate the undesirable edematogenic effect of the luteinizing hormone-releasing hormone (LH-RH) antagonists containing basic D amino acids at position 6, exemplified by [Ac-D-Phe(pCl)1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH [Phe(pCl) indicates 4-chlorophenylalanine], analogs with D-ureidoalkyl amino acids such as D-citrulline (D-Cit) or D-homocitrulline (D-Hci) at position 6 were synthesized and tested in several systems in vitro and in vivo. HPLC analysis revealed that the overall hydrophobicity of the D-Cit/D-Hci6 analogs was similar to that of the basic D-Arg6 antagonists. In vitro, most of the analogs completely inhibited LH-RH-mediated luteinizing hormone release in perfused rat pituitary cell systems at an antagonist to LH-RH molar ratio of 5:1. In vivo, the most active peptides, [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Trp3,D-Cit6,D-Ala10]LH-RH [Nal(2) indicates 3-(2-naphthyl)alanine] and its D-Hci6 analog, caused 100% inhibition of ovulation in cycling rats in doses of 3 micrograms and suppressed the luteinizing hormone level in ovariectomized female rats for 47 hr when administered at doses of 25 micrograms. Characteristically, these peptides did not exert any edematogenic effects even at 1.5 mg/kg. These properties of the D-Cit/D-Hci6 antagonists may make them useful clinically.

Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects

A potent and safe GnRH antagonist has been sought unsuccessfully for the last 2 decades. The recently developed GnRH antagonist RS-26306 or Ganirelix ([N-Ac-D-Nal(2)1,D-pClPhe2,D-Pal(3)3,D-hArg(Et2)6,L-++ +hArg(Et2)8,D-Ala10]GnRH ; Syntex Research, Palo Alto, CA), exhibited high antiovulatory potency and low histamine-releasing properties in preclinical studies. Therefore, we determined the extent to which single sc injections of three doses of RS-26306 (1, 3, and 6 mg) decreased serum concentrations of LH and FSH, the free alpha-subunit of LH/FSH/TSH, PRL, and testosterone in five healthy postmenopausal women. We also examined the pharmacokinetic characteristics of RS-26306 by quantifying serum levels of the drug by RIA. RS-26306 rapidly suppressed serum concentrations of LH, FSH, and free alpha-subunit. RS-26306 (6 mg) maximally decreased serum concentrations (mean +/- SEM) of LH, FSH, and free alpha-subunit by 70.1 +/- 3.6%, 42.3 +/- 2.5%, and 74.6 +/- 3.5%, respectively. RS-26306 also decreased serum testosterone, but not serum PRL, concentrations. RS-26306 concentrations reached peak serum levels at 1.2 +/- 0.3, 1.9 +/- 0.4, and 1.8 +/- 0.5 h, respectively, after 1-, 3-, and 6-mg sc injections. The mean serum half-life values based on the terminal portion of the disappearance curves were 22.8 +/- 2.5 and 26.9 +/- 1.0 h, respectively, after 3- and 6-mg s.c. doses. No systemic side-effects were noted after the administration of RS-26306. Our results demonstrate that the GnRH antagonist RS-26306 has favorable pharmacokinetic characteristics and is a potent suppressor of pituitary gonadotropin secretion in postmenopausal women. These attributes and the lack of systemic side-effects make RS-26306 a promising candidate for future clinical applications.

Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (Ganirelix) with minimal histamine-releasing properties: studies in postmenopausal women.

Reproductive/endocrine and anaphylactoid properties of an LHRH-antagonist, ORF 18260 [Ac−DNAL1(2),4FDPhe2,D-Trp3,D-Arg6]−GnRH

Many methods for assaying the activity and potency of LHRH agonists and antagonists in the female have been developed. Considerably fewer assays have been done in males. Although several good comparisons of LHRH and its analogs have been conducted in male laboratory animals (Labrie et al., 1980), extensive potency studies on the reproductive effects of these peptides have been more conveniently assessed in females because the dosing schedules have been shorter and the endpoints more easily determined. Although the number and variations of the assays used to evaluate LHRH analogs have proliferated, they can be conveniently divided for ease of review into in vitro and in vivo assays.

Biological assays utilized to characterize LHRH and its analogs

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

D. W. Hahn

Author Tools

Chat about Author

Papers

Reproductive/endocrine and anaphylactoid properties of an LHRH-antagonist, ORF 18260 [Ac−DNAL1(2),4FDPhe2,D-Trp3,D-Arg6]−GnRH

Biological assays utilized to characterize LHRH and its analogs