Antagonistic Analogs of Luteinizing Hormone-Releasing Hormone Are Mast Cell Secretagogues

Abstract

The histamine-releasing activity of luteinizing hormone-releasing hormone (LHRH) antagonistic analogs has been documented. Antagonists of LHRH elicited in vitro histamine release from mast cells obtained from previously unexposed rats. Intradermal injection of the antagonists caused increased local skin permeability. Anaphylactoid reactions followed subcutaneous injection of the antagonists and in some cases these edematous reactions were accompanied by increased serum histamine levels. These studies show that these small peptides can cause mast cell degranulation and suggest that the neuropeptide, LHRH, may have modulating effects on the immune system.

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

“…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 (15,16). In addition, these analogs cause a dose-related whealing response (17), increase histamine levels in rats (16), and elicit histamine release from rat mast cells (18).…”

“…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 (15,16). In addition, these analogs cause a dose-related whealing response (17), increase histamine levels in rats (16), and elicit histamine release from rat mast cells (18). The anaphylactoid reactions to these antagonists are not invariably associated with their edematogenic potencies (16) , 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).…”

“…In addition, these analogs cause a dose-related whealing response (17), increase histamine levels in rats (16), and elicit histamine release from rat mast cells (18). The anaphylactoid reactions to these antagonists are not invariably associated with their edematogenic potencies (16) , 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).…”

“…Assays for the edematogenic activity in vivo, cutaneous anaphylactoid reaction in vivo, and histamine-releasing potency in vitro were carried out essentially as described by Morgan et al (16).…”

Selection and Characterization of Mammalian Cell Lines with Stable Over‐Expression of Human Pituitary Receptors for Gonadoliberin

“…Clinical indications are for the treatment of hypogonadotropic hypogonadism, prostate cancer, endometriosis, precocious puberty, polycystic ovarian disease or in assisted fertilization [8]. Initially competitive antagonists of gonadoliberin had serious side effects [30], but new highly potent antagonistic derivatives like CetrorelidSB75 [31-331 are well tolerated and now used in clinical trials. For the identification and characterization of new peptidic or peptidomimetic gonadoliberin derivatives for therapeutic use in humans, the cloning of the human pituitary gonadoliberinreceptor is highly important.…”