Modulating dopamine receptors subtype selectivity by thiophene and benzothiophene based derivatives

Abdel Fattah, Mohamed Assem Omar

In this work we tried to develop new dopaminergic ligands with novel affinity and selectivity profile towards the five different dopamine receptor subtypes; namely D1, D2, D3, D4, and D5 receptors to come up with new medical agents but with fewer side effects relative to those present in the medicinal market such as Haloperidol that is considered to be among the very famous typical antipsychotic agents characterized with Extrapyramidal symptoms adverse effects and Clozapine that represents the atypical antipsychotic agents that suffers agranulocytosis adverse effects. Among the fifty five synthesized ligands, compounds 3, 44a, and 45a were shown to have unique subtype receptor selectivity, thus could be promising atypical antipsychotic agents. Compound 3 was the first azecine derivative to show antagonistic action on both D2 and D5 receptor subtypes, (Ki (D2): 1.5 nM; Ki (D5): 1.9 nM). Compound 44a showed to be more than 200 times more selective to D2 receptors rather than D4 (Ki (D2): 138 nM; Ki (D4):0.62 nM). Compound 45a has shown to be more than 100 times more selective to D3 rather than D2 receptor subtypes and more than 900 times more selective to D4 rather than D2 receptor subtypes (Ki (D2): 28.5 nM; Ki (D3): 0.26 nM; Ki (D4): 0.03 nM).

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Abdel Fattah, Mohamed Assem Omar: Modulating dopamine receptors subtype selectivity by thiophene and benzothiophene based derivatives. 2013.

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