New generation dopaminergic agents.: 6.: Structure-activity relationship studies of a series of 4-(aminoethoxy)indole and 4-(aminoethoxy)indolone derivatives based on the newly discovered 3-hydroxyphenoxyethylamine D2 template

A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D-2(High) and D-2(Low), respectively) of the dopamine (DA) D-2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D-2(High) receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D-2(High) affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D-2 agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D-2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D-2 agonism or antagonism.