Synthesis and preliminary pharmacological investigation of N-lupinyl-2-methoxybenzamides

A set of eleven N-lupinyl-2-methoxybenzamides, variously substituted on the benzene ring, together with two related compounds, were prepared and subjected to a large pharmacological screening, though not all compounds were tested in each assay. Compounds 1-10 displaced [125I]-iodosulpride from D2 receptors only at very high concentration (IC50 > 5 microM). At micromolar concentrations, compounds 1, 12, and 13 inhibited the binding of [3H]-pirenzepine and of [3H]-di-o-tolylguanidine respectively on M1 and sigma receptors; in the last case comp. 13 was more active (IC50 = 0.3 microM) than the epimeric 1. Compounds 1-10 at 10-25 mg/kg p.o. protected mice against electroshock induced seizures; 1-sulpiride was inactive in this test. Compound 1 exhibited in three tests antiarrhythmic activity superior to that of quinidine and lidocaine. The same antagonized, in vitro, guinea pig ileum contractile response induced by several agents, and enhanced the intestinal transit rate in mice (charcoal bolus test). The last activity (shown in lower degree also by comp. 5) could be related to agonism with 5HT4 receptors, as could be expected for orthopramides with conformationally restricted side chains. This possibility is presently under investigation.