| Abstract
| - A series of benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives were preparedand evaluated to determine the necessary requirements for high affinity on the 5-HT4 receptorsand high selectivity versus other receptors. The compounds were synthesized by substitutingthe chlorine atom of benzonaphthyridines and azepinoquinolines with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [3H]GR 113808 as the5-HT4 receptor radioligand. The affinity values (Ki or inhibition percentages) depended uponthe substituent on the aromatic ring on one hand and the substituent on the lateral piperidinechain on the other hand. A chlorine atom produced a marked drop in activity while a N-propylor N-butyl group gave compounds with nanomolar affinities (1 < Ki< 10 nM). Among themost potent ligands (3a, 4a, 5a), 4a was selected on the basis of its high affinity and selectivityfor pharmacological screening and was evaluated in vivo in specific tests. This compound revealsitself as an antagonist/low partial agonist in the COS-7 cells stably expressing the 5-HT4(a)receptor. Derivative 4a also showed in vivo potent analgesic activity in the writhing test atvery low doses.
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