N-substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives asD-2 antagonists/5-HT1A partial agonists with potential as atypical antipsychotic agents

A series of N-substituted 1-(2,3-dihydro-1,4-benzodioxin-2-yl)methylamine d erivatives with D-2 antagonist/5-HT1A partial agonist activity has been pre pared as potential atypical antipsychotic agents. Optimization of in vitro receptor binding activity and in vivo activity in rodent models of psychosi s has led to compound 24, which showed good affinities for human D-2, D-3, and 5-HT1A receptors but significantly less affinity for human alpha(1) adr enoceptors and rat H-1 and muscarinic receptors. In rodents, 24 showed func tional D-2-like antagonism and 5-HT1A partial agonism. After oral dosing, 2 4 showed good activity in rodent antipsychotic tests and very little potent ial to cause extrapyramidal side effects (EPS), as measured by its ability to induce catalepsy in rats only at very high doses. In the light of this p romising profile of activity, 24 has been selected for clinical investigati on as a novel antipsychotic agent with a predicted low propensity to cause EPS.