Stereoselective inhibition of serotonin transporters by antimalarial compounds

Abstract

The serotonin (5-HT) transporter (SERT) is an integral membrane protein that functions to reuptake 5-HT released into the synapse following neurotransmission. This role serves an important regulatory mechanism in neuronal homeostasis. Previous studies have demonstrated that several clinically important antimalarial compounds inhibit serotonin (5-hydroxytryptamine, 5-HT) reuptake. In this study, we examined the details of antimalarial inhibition of 5-HT transport in both Drosophila (dSERT) and human SERT (hSERT) using electrophysiologic, biochemical and computational approaches. We found that the cinchona alkaloids quinidine and cinchonine, which have identical stereochemistry about carbons 8 and 9, exhibited the greatest inhibition of dSERT and hSERT transporter function whereas quinine and cinchonidine, enantiomers of quinidine and cinchonine, respectively, were weaker inhibitors of dSERT and hSERT. Furthermore, SERT mutations known to decrease the binding affinity of many antidepressants affected the cinchona alkaloids in a stereo-specific manner where the similar inhibitory profiles for quinine and cinchonidine (8S,9R) were distinct from quinidine and cinchonine (8R,9S). Small molecule docking studies with hSERT homology models predict that quinine and cinchonidine bind to the central 5-HT binding site (S1) whereas quinidine and cinchonine bind to the S2 site. Taken together, the data presented here support binding of cinchona alkaloids to two different sites on SERT defined by their stereochemistry which implies separate modes of transporter inhibition. Notably, the most potent antimalarial inhibitors of SERT appear to preferentially bind to the S2 site. Our findings provide important insight related to how this class of drugs can modulate the serotonergic system as well as identify compounds that may discriminate between the S1 and S2 binding sites and serve as lead compounds for novel SERT inhibitors.

Biologically active quinoline and quinazoline alkaloids part II

“…These results indicated that distinct cinchona alkaloids bind to two different sites on SERT, with the most potent antimalarial inhibitors of SERT appearing to preferentially bind to the S2 site. This difference implies separate modes of transporter inhibition …”

“…Studies in 2014 showed that quinine significantly inhibited breast cancer resistance protein (BCRP) mediated and P‐gp‐mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range, and inhibited adenosine triphosphate (ATP) binding cassette transporter activity . Quinidine and cinchonine, which have identical stereochemistry at carbons 8 and 9, exhibited stronger inhibition of human and Drosophila melanogaster serotonin receptor transporter (hSERT and dSERT) function than their enantiomers, quinine, and cinchonidine . Furthermore, quinine and cinchonidine bound to the central receptor binding site (S1), whereas quinidine and cinchonine bound to the S2 site in small molecule docking studies.…”

“…80 Quinidine and cinchonine, which have identical stereochemistry at carbons 8 and 9, exhibited stronger inhibition of human and Drosophila melanogaster serotonin receptor transporter (hSERT and dSERT) function than their enantiomers, quinine, and cinchonidine. 81 Furthermore, quinine and cinchonidine bound to the central receptor binding site (S1), whereas quinidine and cinchonine bound to the S2 site in small molecule docking studies. These results indicated that distinct cinchona alkaloids bind to two different sites on SERT, with the most potent antimalarial inhibitors of SERT appearing to preferentially bind to the S2 site.…”

“…This difference implies separate modes of transporter inhibition. 81 Among quinoline alkaloids reported with antimalarial activity between 2009 and 2016, examples are 6-methoxy-7-hydroxydictamnine, 36 4-methoxy-1-methylquinolin-2-one, 82 (2 ′ R)-2 ′ ,3 ′ -epoxy-N-methylatanine, 83 kokusaginine, 84 and maculosidine. 85 Nitidine (106) ( Figure 14) from Toddalia asiatica exhibited high antiplasmodial activity with an IC 50 of 0.045 g/mL against the K39 strain of P. falciparum in vitro and likely acts by a similar mechanism of that of chloroquine.…”

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…Langiferin and morin were found to protect neurons against excitotoxic neuronal death, which was associated with downregulation of NF-kB (CamposEsparza et al, 2009). Isoquercetin protected cultured cortical neurons from oxygen-glucose deprivation via suppression of the Toll-like receptor 4/NF-kB signaling pathway (Beckman et al, 2013). A neuroprotective effect of silymarin on LPS-induced neurotoxicity was reported in mesencephalic mixed neuron-glia cultures.…”