Tetracyclic analogues of [+]-S 14297: Synthesis and determination of affinity and selectivity at cloned human dopamine D3 vs D2 receptors

Starting from the structure of the preferential D3 antagonist S 14297 (1), we have prepared a series of cis and trans tetracyclic derivatives of general formula I in order to improve potency and selectivity for D3 receptors. The trans oxazino derivative 2c, showed slightly increased affinity at D3 receptors and double the selectivity for D3 over D2 receptors, in comparison to S 14297. Cis derivatives and compounds where R1 is aralkyl were totally devoid of activity.