We have carried out a structural exploration of (2S,4R,5R)-2-(bis(4-fluorophenyl)methyl)-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-473) to investigate the influence of various functional groups on its aromatic ring, the introduction of heterocyclic aromatic rings, and the alteration of the stereochemistry of functional group on the pyran ring. The novel compounds were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting monoamine neurotransmitter uptake. Our studies identified some of the most potent dopamine-norepinephrine reuptake inhibitors known to-date like D-528 and D-529. The studies also led to development of potent triple reuptake inhibitors such as compounds D-544 and D-595. A significant influence from the alteration of the stereochemistry of the hydroxyl group on the pyran ring of D-473 on transporters affinities was observed indicating stereospecific preference for interaction. The inhibitory profiles and structure-activity relationship of lead compounds were further corroborated by molecular docking studies at the primary binding sites of monoamine transporters. The nature of interactions found computationally correlated well with their affinities for the transporters.
Keywords: Triple reuptake inhibitors; attention-deficit hyperactivity disorder; dopamine−norepinephrine reuptake inhibitor; homology modeling; pharmacotherapy; post-traumatic stress disorder.