Potential antipsychotic agents 5. Synthesis and antidopaminergic properties of substituted 5,6-dimethoxysalicylamides and related compounds.
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.
Högberg
T
T
Astra Research Centre AB, CNS Research & Development, Södertälje, Sweden.
Bengtsson
S
S
de Paulis
T
T
Johansson
L
L
Ström
P
P
Hall
H
H
Ogren
S O
SO
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis*; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D018492:Dopamine Antagonists; D008297:Male; D020891:Raclopride; D051381:Rats; D011919:Rats, Inbred Strains; D012457:Salicylamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D012457:Salicylamides; D020891:Raclopride; D013134:Spiperone; D001058:Apomorphine