Serotonergic aporphine derivatives : Synthesis and structure-activity relationships

Abstract: Novel series of well-characterized and stereochemically pure 11-substituted (R)-aporphine derivatives have been prepared and their interaction with serotonin 5-HT7 and 5-HT1A receptors and dopamine D2A and D1 receptors have been studied. Efficient palladium catalyzed reactions were utilized for the diastereoselective synthesis of atropisomers as well as for the synthesis of several of the other (R)-aporphine derivatives. A number of 11-arylated (R)-aporphines displayed high affinity for 5-HT7 and 5-HT1A receptors and derivatives with selectivity for either 5-HT7 or 5-HT1A receptors were obtained by chosing the proper substituents on the 11-phenyl ring. Simultaneous substitution of the 2' and 6' positions of (R)-11-phenylaporphine afforded derivatives, including some atropisomers, with increased 5-HT7 selectivity and several of these analogues were characterized as selective 5-HT7 receptor antagonists. Introduction of substituents in the other positions of the 11-phenyl group resulted in derivatives with selectivity for 5-HT1A receptors. In addition, new series of novel pentacyclic (R)-aporphines were synthesized either by the introduction of a methylene group between carbon atoms C1 and C11 in the (R)-aporphine skeleton or by ring expansion reactions of (R)-1,11-carbonylaporphine. These series of derivatives afforded the possibility to introduce substituents/functional groups below, above and in the plane of the ring system thereby allowing for structural extensions into previously unexplored areas of receptor binding sites. Compounds with various affinities for the serotonin and dopamine receptors were obtained and novel 5-HT7 receptor antagonists were identified.The identification of selective serotonin 5-HT7 receptor antagonists is of particular interest since only a few putatively selective 5-HT7 receptor antagonistic ligands have been reported.