Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5,6-dimethoxysalicylamides and related compounds

Abstract

A series of 3-substituted 5,6-dimethoxysalicylamides III (9-13 and 15) has been synthesized from the corresponding 2,5,6-trimethoxybenzoic acids. Relaxation times T1 and carbon chemical shifts of the methoxy groups in III showed that the 6-methoxy group adopts a nearly perpendicular orientation and the 5-methoxy group takes on a more coplanar orientation with respect to the ring plane in solution. The salicylamides III display a very high and stereoselective affinity for the [3H]spiperone and [3H]raclopride binding sites in vitro. Regioisomeric salicylamides IV also exhibit pronounced, but lower than III, affinity for the [3H]spiperone binding site. The structural requirements were further assessed by studies of the related amino analogues 23 and 24 and hydroxy analogue 27. The 3-bromo compound 11 (FLB 463) was studied in various in vivo models and compared with the dopamine-D2 antagonists sulpiride, raclopride, eticlopride, and haloperidol. The high potency of 11 to selectively block dopamine-D2 receptors in vitro and in vivo combined with indications on a low potential for motor side effects makes it a very interesting new member of the class of substituted salicylamides.