title: The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats.
abstract: Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.
authors.affiliation: CURE/Digestive Diseases Research Center, Department of Medicine, Division of Digestive Diseases, The David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America ; Oppenheimer Family Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, The David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America ; VA Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Million
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Zhao
authors.forename: Andrew
authors.initials: A
authors.lastname: Luckey
authors.forename: József
authors.initials: J
authors.lastname: Czimmer
authors.forename: George D
authors.initials: GD
authors.lastname: Maynard
authors.forename: John
authors.initials: J
authors.lastname: Kehne
authors.forename: Diane C
authors.initials: DC
authors.lastname: Hoffman
authors.forename: Yvette
authors.initials: Y
authors.lastname: Taché
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000503:physiopathology; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D003672:Defecation / Q000187:drug effects; D003967:Diarrhea / Q000503:physiopathology / Q000517:prevention & control; D004336:Drug Antagonism; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D007441:Intubation, Gastrointestinal; D043183:Irritable Bowel Syndrome / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D015394:Molecular Structure; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology; D014781:Viscera / Q000187:drug effects* / Q000503:physiopathology; D000099052:CRF Receptor, Type 1
chemical_list: C000589189:5-(6-isopropyl-2-methylaminopyridin-3-yl)-(N-(1-ethyl)propyl)-3-methoxy-6-methylpyrazine-2-amine; C561056:N-(1-ethylpropyl)-(3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl)amine; D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
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