Serotoninergic properties of new conformationally restricted benzamides

Summary 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 C 3 , C 4 , C 5 and C 6 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 D 2 , 5-HT 3 and 5-HT 4 receptors. The results show a marked increase in the selectivity and potency of these derivatives for 5-HT 3 receptors with regard to metoclopramide (compound 1d : 5-HT 3 K i = 9.03 nM; 5-HT 4 K i > 5000; D 2 K i > 5000). The influences of steric hindrance and hydrophobic properties on the affinity of benzamide derivatives for 5-HT 3 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-HT 3 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-HT 3 receptor antagonists. On the other hand, the hydrophobic parts of the basic moieties had different spatial occupancies.