dinoprostone and Disease-Models--Animal

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH

Topics: Amino Alcohols; Animals; Anticonvulsants; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Mice; Models, Molecular; Molecular Structure; Rats; Seizures; Structure-Activity Relationship

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

The "reduced in osteosclerosis" transporter (Roct), which shows decreased expression in the osteosclerosis (oc) mutant mouse, has high homology with rat and human organic anion transporter 3 (OAT3). However, its transport properties and involvement in bone turnover are poorly understood. Here, we examined Roct-mediated transport using a Xenopus laevis oocyte expression system. Roct-expressing oocytes exhibited uptake of [(3)H]estrone sulfate, [(3)H]p-aminohippuric acid, [(3)H]benzylpenicillin, [(3)H]estradiol 17beta-glucronide, [(3)H]indoxyl sulfate, [(14)C]indomethacin, [(3)H]homovanillic acid, [(3)H]cimetidine, [(14)C]glutarate, [(14)C]salicylic acid, and [(3)H]methotrexate. Furthermore, the uptake of [(3)H]benzylpenicillin by Roct coexpressed with Na(+)-dicarboxylate cotransporter was trans-stimulated by glutarate preloading, and [(3)H]estrone sulfate uptake showed a similar tendency, suggesting that Roct is a dicarboxylate exchanger. [(3)H]Benzylpenicillin uptake by Roct was inhibited by OAT3 substrates and inhibitors, and by sulfate or glucuronide conjugates, and compounds involved in bone turnover. Roct mRNA is expressed abundantly in the kidney and was also detected in the brain, choroid plexus, and eye. Immunohistochemical analysis revealed that Roct is localized in brain capillary endothelial cells. These results indicate that the transport properties and tissue distribution of Roct are similar to those of OAT3, suggesting that Roct functions as mouse OAT3. Because Roct is expressed in the kidney and at the blood-brain barrier, it may play a role in the excretion of substrates such as conjugates and bone turnover factors.

Topics: Animals; Biological Transport; Blood-Brain Barrier; Capillaries; Disease Models, Animal; Estrone; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Osteosclerosis; Penicillin G; RNA, Messenger