title: New benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives as selective antagonists of 5-HT4 receptors: binding profile and pharmacological characterization.
abstract: A series of benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives were prepared and evaluated to determine the necessary requirements for high affinity on the 5-HT(4) receptors and high selectivity versus other receptors. The compounds were synthesized by substituting the chlorine atom of benzonaphthyridines and azepinoquinolines with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR 113808 as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) depended upon the substituent on the aromatic ring on one hand and the substituent on the lateral piperidine chain on the other hand. A chlorine atom produced a marked drop in activity while a N-propyl or N-butyl group gave compounds with nanomolar affinities (1 < K(i) < 10 nM). Among the most potent ligands (3a, 4a, 5a), 4a was selected on the basis of its high affinity and selectivity for pharmacological screening and was evaluated in vivo in specific tests. This compound reveals itself as an antagonist/low partial agonist in the COS-7 cells stably expressing the 5-HT(4(a)) receptor. Derivative 4a also showed in vivo potent analgesic activity in the writhing test at very low doses.
authors.affiliation: ATBI, Université de Caen, 5 rue Vaubénard, 14032 Caen Cedex, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Hinschberger
authors.forename: Sabrina
authors.initials: S
authors.lastname: Butt
authors.forename: Véronique
authors.initials: V
authors.lastname: Lelong
authors.forename: Michel
authors.initials: M
authors.lastname: Boulouard
authors.forename: Aline
authors.initials: A
authors.lastname: Dumuis
authors.forename: François
authors.initials: F
authors.lastname: Dauphin
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000096:biosynthesis; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
chemical_list: C470656:5-((N-propylpiperidin-4-yl)methoxy)-1,2,3,4-tetrahydrobenzo(h)(1,6)naphthyridine; D009287:Naphthyridines; D011804:Quinolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D000242:Cyclic AMP