Structure‐Based Identification of Aporphines with Selective 5‐HT_2A Receptor‐Binding Activity

Abstract

Selective blockade of the serotonin 5-HT(2A) receptor is a useful therapeutic approach for a number of disorders, including schizophrenia, insomnia and ischaemic heart disease. A series of aporphines were docked into a homology model of the rat 5-HT(2A) receptor using AutoDock. Selected compounds with high in silico binding affinities were screened in vitro using radioligand-binding assays against rat serotonin (5-HT(1A) and 5-HT(2A)) and dopamine (D1 and D2) receptors. (R)-Roemerine and (±)-nuciferine were found to have high affinity for the 5-HT(2A) receptor (K(i) = 62 and 139 nM, respectively), with (R)-roemerine showing 20- to 400-fold selectivity for the 5-HT(2A) receptor over the 5-HT(1A), D1 and D2 receptors. Investigation into the ligand-receptor interactions suggested that the selectivity of (R)-roemerine is due to it having stronger H-bonding and dipole-dipole interactions with several of the key residues in the 5-HT(2A) receptor-binding site.

Molecular Modeling of 5HT2A Receptor – Arylpiperazine Ligands Interactions

“…These two interactions establish a correct ligand orientation: tail part binds into the nearby binding pocket formed by Leu 123, Ser 159, Trp 336, Phe 339, Val 366, and Tyr 370, while the head part fits into the second binding pocket formed by Trp 151, Ile 152, Leu 229, Ala 230, Phe 234, and Val 235. Those findings are supported at least in part, by experimental results, as Asp 155, Ser 159, Trp 336, Phe 339, and Tyr 370 were previously determined by a point mutation study as key amino acid residues for high 5HT 2A affinity.…”

“…Molecular docking was performed in AUTODOCK Vina 1.1.1 (20). The grid box dimensions were set to 22 9 22 9 22 A 3 , and its center was set to span all crucial amino acid residues identified according to previous studies (21)(22)(23)(24)(25). Exhaustiveness was set to 100.…”

Parkinson's disease, visual hallucinations and apomorphine: A review of the available evidence

“…This piperidine moiety is also incorporated in the chemical structure of many antipsychotic medications, including piperidine phenothiazines, haloperidol, risperdone, bulbocapnine and other aporphines [75,76]. Based on the structural similarities, it has been argued that the antipsychotic potential of apomorphine is due to the specific action of this piperidine moiety in binding to dopaminergic and serotonergic receptors (particularly 5-HT2A-receptors), producing an antagonistic effect [9,12,[76][77][78].…”

“…In other words, the optimal prefrontal performance is achieved with intermediate dopaminergic activity and whether stimulation or inhibition of D1-like receptors yields this optimum depends on the baseline dopaminergic activity in the prefrontal cortex. Enhanced dopamine levels are found in early PD patients resulting in impaired prefrontal functioning [78][79][80] presumably due to frontal compensation [81]. With disease progression, the number of prefrontal D1-like receptors is reduced and prefrontal functioning deteriorates [80,[82][83][84].…”

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

“…Several aporphine compounds have previously been demonstrated to impair neuromuscular function in a variety of helminth parasites (Ayers et al., 2007, Chan et al., 2014, Lin et al., 2014), although the molecular target of these drugs in parasites is uncharacterized. The affinity of aporphinoids for mammalian 5-HT GPCRs (Munusamy et al., 2013, Ponnala et al., 2014, Ponnala et al., 2015, Farrell et al., 2016) was especially intriguing to us in this context. Here, we examine the action of four aporphinoid natural products at Sm.5HTR L and demonstrate a close correlation between receptor blockade and a hypomotive action on schistosome larvae and adults.…”