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Research Themes Drug discovery

Drug Discovery: Antidepressant Potential of 6-NQ SERT Inhibitors

SBKB [doi:10.1038/sbkb.2012.163]
Featured Article - October 2013
Short description: Molecular docking models are combined with in vitro and in vivo assays to evaluate the therapeutic potential of 6-nitroquipazine analogs as antidepressants.

Homology model docking results showing the orientation of a long-chain 6-NQ analog in the binding pocket of SERT in the outward-facing conformation. Amino acids within the binding pocket are shown in stick representation, and the analog is in yellow. Figure courtesy of Ingebrigt Sylte.

Serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) are integral membrane proteins that share the transmembrane α-helical structure characteristic of the Na+-coupled transporter family. Located in presynaptic neurons, they play a key role in regulating neurotransmission by removing 5-HT from the synaptic cleft, a process known as reuptake.

SERTs are the target of two classes of antidepressant drugs that inhibit their activity, the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, 6-nitroquipazine compounds (6-NQ), traditionally used for radiolabeling studies, also have unexplored potential as therapeutic agents, as they bind SERT with higher affinity than either TCAs or SSRIs. Moreover, dual-action 6-NQ analogs target the autoinhibitory 5-HT1A receptors that reduce serotonergic transmission and thereby delay the onset of antidepressant drug action. Sylte and colleagues, including Abagyan (PSI GPCR and CHSAM), thus synthesized and analyzed the in vitro SERT and 5-HT1A-binding affinities of 12 dual-acting 6-NQ alkyl analogs by radioligand competition assays. While all displayed low affinity for 5-HT1A, SERT affinities were in the nanomolar range and increased with analog chain length. When five of the highest-affinity SERT binders were subsequently tested for antidepressant activity in mice using forced swim and locomotor activity tests, three long-chain analogs showed moderate antidepressant effects.

Using a SERT homology model generated from the crystal structure of the prokaryotic LeuT transporter in the outward-facing conformation (PDB 3F3A), interactions with the 6-NQ analogs were compared. Docking all 12 compounds into the ligand-binding pocket revealed that the analogs bound in one of two opposite orientations. In one orientation, longer alkyl chains had a potential to form hydrophobic interactions that would enhance binding affinity. However, because the docking analysis is limited by the flexibility of the 6-NQ ligands, the docking scores of the SERT-ligand complexes do not reflect the measured binding affinities, and contributions to ligand affinity must be further addressed by other methods. In contrast, the measured 5-HT1A-binding affinities were in agreement with docking studies obtained with a 5-HT1A homology model based on the crystal structure of the β2-adrenergic receptor (PDB 3NYA). Together, these results suggest that structure-based approaches may prove valuable tools for evaluating the efficacy of these compounds in blocking receptor function and their potential contributions to therapeutic strategies.

Beth Moorefield


  1. M. Gabrielsen et al. Synthesis, antidepressant evaluation and docking studies of long-chain alkylnitroquipazines as serotonin transporter inhibitors.
    Chem Biol Drug Des. 81, 695-706 (2013). doi:10.1111/cbdd.12116

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