| Abstract
| - A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 weresynthesized and evaluated for their affinity for both the high- and low-affinity agonist states(D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives(i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. Theindolones 8 were observed to have high affinity for the D2High receptor. Comparison of theirpreviously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealedthe chroman analogues to be more potent, whereas little loss in D2High affinity was observedwhen comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Severalregions of the phenoxyethylamine framework were modified and recognized as potential sitesto modulate the level of intrinsic activity. A conformational analysis was performed and aputative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophorecriteria based on the McDermed model. Structure−activity relationships gained from thesestudies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels.These agents should be of therapeutic value in treating disorders resulting from hypo- andhyperdopaminergic activity, without the side effects associated with complete D2 agonism orantagonism.
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