Dopamine/serotonin receptor ligands. Part 17: A cross-target SAR approach: Affinities of azecine-styled ligands for 5-HT2A versus D1 and D2 receptors

Dibenzo- and benzindolo-azecines represent a novel class of high-affinity dopamine receptor antagonists. To further characterize these drugs as potential neuroleptics, we selected a set of azecine derivatives and ring expanded homologues and we measured their antagonist activity at the 5-HT2A receptor in the porcine coronary artery. SARs found for the 5-HT2A receptor resemble those for the D1 but not the D2 receptor. The protein–ligand interactions were discussed with respect to the different binding pockets.

Graphical abstractA cross-target SAR was conducted with 13 azecine-styled compounds on D1, D2 and 5-HT2A receptors. Surprisingly, molecular modifications affect the affinity for the D1 receptor in the same manner as the 5-HT2A receptor. The protein–ligand interactions were discussed with respect to the different binding pockets.Figure optionsDownload full-size imageDownload as PowerPoint slide