Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HT7AR ligands

Bioorg Med Chem. 2020 Aug 1;28(15):115578. doi: 10.1016/j.bmc.2020.115578. Epub 2020 Jun 5.


Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HT1AR, 5-HT2AR, 5-HT6R and 5-HT7AR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HT7AR and also had moderate 5-HT7AR affinity. Compounds from the C10 N-monosubstituted series generally lacked affinity for 5-HT2AR and 5-HT6R and showed strong affinity for 5-HT1A or 5-HT7AR. Compounds in this series that contained an N6-methyl group were up to 27-fold selective for 5-HT7AR over 5-HT1AR, whereas compounds with an N6-propyl substituent showed a reversal in this selectivity. The C10 benzofused aminothiazole analogues showed a similar binding profile as the C10 N-monosubstituted series i.e. strong affinity for 5-HT1AR or 5-HT7AR, with selectivity between the two receptors being similarly influenced by N6-methyl or N6-propyl substituents. Compounds 29 and 34a exhibit high 5-HT7AR affinity, excellent selectivity versus dopamine receptors and function as antagonists in 5-HT7AR cAMP-based assays. Compounds 29 and 34a have been identified as new lead molecules for further tool and pharmaceutical optimization.

Keywords: 5-HT(1A); 5-HT(7); Aporphine; CNS; Dopamine; SAR; Serotonin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aporphines / chemical synthesis
  • Aporphines / metabolism
  • Aporphines / pharmacology*
  • Cell Line
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacology*
  • Structure-Activity Relationship


  • Aporphines
  • Ligands
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 7 receptor