Design, synthesis and evaluation of benzo[a]thieno[3,2-g]quinolizines as novel l-SPD derivatives possessing dopamine D1, D2 and serotonin 5-HT1A multiple action profiles

Abstract A novel scaffold derived from l -SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D 1 , D 2 and D 3 ) and serotonin (5-HT 1A and 5-HT 2A ) receptors. Most of the tetracyclic compounds exhibited higher affinities for D 2 and 5-HT 1A receptors than l -SPD, while compound 23e showed the highest K i value of 7.54 nM at D 2 receptor which was 14 times more potent than l -SPD. Additionally, compounds 23d and 23e were more potent than l -SPD at D 3 receptor. According to the functional assays, 23d and 23e were demonstrated as full antagonists at D 1 and D 2 receptors and full agonists at 5-HT 1A receptor. Since the combination of D 2 antagonism and 5-HT 1A agonism is considered effective in treating both the positive and negative symptoms of schizophrenia, these novel compounds are implicated as potential therapeutic agents.