SEROTONINERGIC PROPERTIES OF NEW CONFORMATIONALLY RESTRICTED BENZAMIDES

A new series of benzamides derived from metoclopramide have been synth esized, 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 diamin o derivatives were prepared through Strecker's reaction from the corre sponding 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-HT3 and 5-HT4 receptors. The resul ts show a marked increase in the selectivity and potency of these deri vatives for 5-HT3 receptors with regard to metoclopramide (compound 1d : 5-HT3 K-i = 9.03 nM; 5-HT4 K-i > 5000; D-2 K-i > 5000). The influenc es of steric hindrance and hydrophobic properties on the affinity of b enzamide derivatives for 5-HT3 receptors were also emphasized by these data. The X-ray crystal structure of compound 1d was compared with th at of the minimal energy conformer of BRL 24682, a reference 5-HT3 rec eptor 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-H T3 receptor antagonists. On the other hand, the hydrophobic parts of t he basic moieties had different spatial occupancies.