In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation.
Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator. CRH receptors (CRH-R1, R2alpha, R2beta) exhibit a specific tissue distribution. Antalarmin, a novel pyrrolopyrimidine compound, displaced 12SI-oCRH binding in rat pituitary, frontal cortex and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmnin (20 mg/kg body wt.) significantly inhibited CRH-stimulated ACTH release and carageenin-induced subcutaneous inflammation in rats. Antalarmin, or its analogs, hold therapeutic promise in disorders with putative CRH hypersecretion, such as melancholic depression and inflammatory disorders.
Webster
E L
EL
Pediatric Endocrinology Section, DEB, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
Lewis
D B
DB
Torpy
D J
DJ
Zachman
E K
EK
Rice
K C
KC
Chrousos
G P
GP
D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002351:Carrageenan / Q000008:administration & dosage / Q000494:pharmacology; D002531:Cerebellum / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007279:Injections, Subcutaneous; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012756:Sheep
D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D002351:Carrageenan; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone