u-50488 and Peritonitis

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

Fedotozine is a peripheral opioid agonist. Its effects were assessed in experimental ileus in rats.. Ileus was induced by abdominal surgery (laparotomy and cecum palpation) or peritonitis (acetic acid, intraperitoneally). Digestive motility was recorded by electromyography and gastrointestinal transit estimated using a 51Cr-labeled test meal.. Surgery or peritonitis inhibited motility and migrating myoelectrical complexes for 2-3 hours. In both models, fedotozine (3 mg/kg, intravenously; 10 mg/kg, subcutaneously) restored a normal motility pattern. This action was reproduced by the kappa-agonist, U-50, and 488H and was blocked by subcutaneous naloxone, naloxone-methiodide, or nor-binaltorphimine, a selective kappa-antagonist. Peritonitis induced a 57% inhibition of gastric emptying and intestinal transit that was reversed by fedotozine (1-10 mg/kg, subcutaneously) or kappa-agonists (U-50, 488H, bremazocine) but not delta-agonists (DPDPE, [D-Ala2]-deltorphin-II), whereas mu-agonists (morphine, fentanyl) potentiated ileus. Fedotozine restoration of transit was blocked by subcutaneous naloxone, naloxone-methiodide, or norbinaltorphimine but not by intracerebroventricular naloxone. Fedotozine was inactive up to 300 micrograms/rat when given intracerebroventrically or intrathecally.. Fedotozine reverses experimental ileus via an action at peripheral kappa-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Abdomen; Animals; Benzyl Compounds; Gastric Emptying; Gastrointestinal Motility; Intestinal Obstruction; Male; Naloxone; Peritonitis; Propylamines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa