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

Abstract

To eliminate the undesirable edematogenic effect of the lutemizing hormone-releasing hormone (LH- Since the isolation and structural elucidation of hypothalamic luteinizing hormone-releasing hormone (LH-RH) more than 2000 analogs have been synthesized, in view of their expected medical applications (1). Chronic administration of potent LH-RH agonists leads to the inhibition of pituitary and gonadal functions (2-6). While repeated administration of LH-RH agonists is required to lower the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroids, similar effects can be obtained with single administration of LH-RH antagonists (7). Competitive antagonists of LH-RH were developed by multiple modification of the parent molecule, <Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-ProGly-NH2 (8)(9)(10)(11)(12)(13)(14) (<Glu, pyroglutamic acid). Agonist activity is reduced by substitution of aromatic D amino acids at positions 2 and 3, and receptor affinity is retained when there are replacements at residues 1 and 6, and in some analogs also in position 10. LH-RH antagonists are frequently character- , was reported to be 1/10th as potent as I in releasing histamine and showed no edematogenic effect in the rat at the doses tested (0.5-1.0 mg/kg) (14). Antagonist H, which induced edema at the challenge dose of 1.5 mg/kg, was also about 1/10th as potent in histamine release assays as the other hydrophilic antagonists studied (16).RHIn contrast to hydrophilic antagonists, hydrophobic antagonists having a neutral aromatic D amino acid at position 6, for instance

Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca 2+ -dependent pathway

“…LHRH agonist [D-Trp-6]-LHRH and LHRH antagonist SB-75 (Cetrorelix), originally synthesized in the laboratory of A.V.S. (42,43), were made by Debiopharm (Lausanne, Switzerland) and Asta Medica (Frankfurt am Main, Germany), respectively. Nifedipine, EDTA, DMSO, and propidium iodide (PI) were purchased from Sigma, and Fluo-3 acetoxymethyl ester (AM) and Annexin V-FITC were obtained from Molecular Probes and BD Pharmingen, respectively.…”

High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines

“…LHRH) was prepared as described previously (14,15 Hoe-013 (Ac-D-Nal-D-(pCl)-Phe-D-Trp-Ser-Tyr-D-Ser(Rha)-Leu-Arg-ProAzagly-NH2) (Ramorelix) was kindly provided by Dr. H. H. Sedlacek, Behringwerke, Marburg, Germany.…”

Characterization of a Thermostable d -Stereospecific Alanine Amidase from Brevibacillus borstelensis BCS-1

“…The enzyme was inhibited by dithiothreitol, 2-mercaptoethanol, and EDTA yet was strongly activated by Co 2؉ and Mn 2؉ . The k cat /K m for D-alaninamide was measured as 544.4 ؎ 5.5 mM ؊1 min ؊1 at 50°C with 1 mM Co 2؉ .D-Amino acids occur in bacterial cell wall peptidoglycan (28), mammalian cells (11), higher plants (25), and active peptides (5,13,14,24) and are important materials for various pharmaceuticals, herbicides, and food additives (1). Unlike L-amino acids, almost all D-amino acids are obtained by using enzymatic methods; otherwise it is difficult to obtain a high state of optical purity and productivity (1,22).…”