THE SEROTONIN 5-HT4 RECEPTOR .1. DESIGN OF A NEW CLASS OF AGONISTS AND RECEPTOR MAP OF THE AGONIST RECOGNITION SITE

The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimida mide are presented. A conformational study of the 5-HT4 receptor agoni sts serotonin and zacopride led to the identification of an initial ph armacophore and to the definition of a three-dimensional map of the 5- HT4 agonist recognition site. 1, a representative member of our new cl ass of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent , full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD(2) value of 8.8, d isplaying selectivity (ranging from 40-to over 10 000-fold) versus oth er members of the serotonin receptor family.