New 2-thioether-substituted apomorphines as potent and selective dopamine D2 receptor agonists

A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3-mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a–g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D2 full agonists equipotent with apomorphine (1) having significantly increased D2/D1 selectivity ratios.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of novel apomorphine derivatives with diversely functionalized aminoalkyl side chains in the proximity of position 2 of the aporphine skeleton. ► A thiopyrano-fused byproduct was also isolated and characterized. ► Neuropharmacologically characterization revealed that two derivatives have equipotent D2 full agonists with apomorphine (1) having significantly increased D2/D1 selectivity ratio.