Serotoninergic properties of new conformationally restricted benzamides

Article abstract of DOI:10.1016/0223-5234(96)89139-2

A new series of benzamides derived from metoclopramide have been synthesized, in which the vicinal carbon of the basic nitrogen atom of the ethyl chain is situated on the C₃, C₄, C₅ and C₆ rings. The diamino derivatives were prepared through Strecker's reaction from the corresponding ketones except for the cyclopropyl derivatives where 1-ethoxy-1-trimethylsiloxy cyclopropane was used as the starting material. The benzamides were prepared using the mixed anhydride method. They were tested in binding assays for D₂, 5-HT₃ and 5-HT₄ receptors. The results show a marked increase in the selectivity and potency of these derivatives for 5-HT₃ receptors with regard to metoclopramide (compound 1d: 5-HT₃ K(i) = 9.03 nM; 5-HT₄ K(i) > 5000; D₂ K(i) > 5000). The influences of steric hindrance and hydrophobic properties on the affinity of benzamide derivatives for 5-HT₃ receptors were also emphasized by these data. The X-ray crystal structure of compound 1d was compared with that of the minimal energy conformer of BRL 24682, a reference 5-HT₃ receptor antagonist benzamide, determined using the Random Search program. Superimposition of the two structures showed a suitable fit between the pharmacophore groups previously determined to be important for 5-HT₃ receptor antagonists. On the other hand, the hydrophobic parts of the basic moieties had different spatial occupancies.