Mapping the binding pocket of a novel, high-affinity, slow dissociating tachykinin NK3 receptor antagonist: Biochemical and electrophysiological characterization

Malherbe, Pari; Knoflach, Frédéric; Marcuz, Anne; Bohnert, Claudia; Weber, Michaël; Knust, Henner; Ratni, Hasane; Spooren, Will; Ballard, Theresa M.; Bissantz, Caterina

doi:10.1016/j.neuropharm.2014.07.017

Cited by 7 publications

(6 citation statements)

References 55 publications

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“…The results of CoMFA model can be visualized as stereochemical and electrostatic contour maps. For better interpretation, these maps are showed for the most (19) and the least active (6) compounds ( Figure 6). Stereochemical contours are depicted in green (favored) and yellow (disfavored), while electrostatic fields are shown in red (negative charges enhancing the activity) and blue (positive charges enhancing the activity).…”

Section: Qsar Models Physicochemical Interpretationmentioning

confidence: 99%

“…The exact distribution of this receptor in the brain is still unknown, but it seems to be found predominantly in cortical regions such as the frontal and parietal cortex, and also in the hippocampus [3][4][5] . Data from pre-clinical and clinical trials of non-peptide NK 3 antagonists used to treat schizophrenia have shown positive effects, with significant reduction of symptoms and lack of major side effects 3,[6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

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Understanding Miltefosine–Membrane Interactions Using Molecular Dynamics Simulations

et al. 2015

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Coarse-grained molecular dynamics simulations are used to calculate the free energies of transfer of miltefosine, an alkylphosphocholine anticancer agent, from water to lipid bilayers to study its mechanism of interaction with biological membranes. We consider bilayers containing lipids with different degrees of unsaturation: dipalmitoylphosphatidylcholine (DPPC, saturated, containing 0%, 10%, and 30% cholesterol), dioleoylphosphatidylcholine (DOPC, diunsaturated), palmitoyloleoylphosphatidylcholine (POPC, monounsaturated), diarachidonoylphosphatidylcholine (DAPC, polyunsaturated), and dilinoleylphosphatidylcholine (DUPC, polyunsaturated). These free energies, calculated using umbrella sampling, were used to compute the partition coefficients (K) of miltefosine between water and the lipid bilayers. The K values for the bilayers relative to that of pure DPPC were found to be 5.3 (DOPC), 7.0 (POPC), 1.0 (DAPC), 2.2 (DUPC), 14.9 (10% cholesterol), and 76.2 (30% cholesterol). Additionally, we calculated the free energy of formation of miltefosine-cholesterol complexes by pulling the surfactant laterally in the DPPC + 30% cholesterol system. The free energy profile that we obtained provides further evidence that miltefosine tends to associate with cholesterol and has a propensity to partition into lipid rafts. We also quantified the kinetics of the transport of miltefosine through the various bilayers by computing permeance values. The highest permeance was observed in DUPC bilayers (2.28 × 10(-2) m/s) and the lowest permeance in the DPPC bilayer with 30% cholesterol (1.10 × 10(-7) m/s). Our simulation results show that miltefosine does indeed interact with lipid rafts, has a higher permeability in polyunsaturated, loosely organized bilayers, and has higher flip-flop rates in specific regions of cellular membranes.

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Section: Qsar Models Physicochemical Interpretationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Understanding Miltefosine–Membrane Interactions Using Molecular Dynamics Simulations

et al. 2015

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“…34,43 Variant rs144292455 causes idiopathic hypogonadotropic hypogonadism in male homozygotes 34 and the rare allele shows additive effects, delaying menarche by 1·25 years in female heterozygotes 13,35 , an effect confirmed in our study cohort despite the lack of association with VMS. One explanation for these apparently contradictory results could be that complete inhibition of NK3R signalling 45 might be required to reduce VMS, and that the heterozygous women in our analyses still had sufficient NKB/NK3R signalling to cause VMS, resulting in no discernible reduction in symptoms. In contrast, we suggest that puberty timing appears to be sensitive to the amount of NKB/NK3R signalling.…”

Section: Discussionmentioning

confidence: 74%

Genomic insights into the mechanism of NK3R antagonists for treatment of menopausal vasomotor symptoms

Ruth

Beaumont

Locke

et al. 2022

Preprint

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BackgroundMenopausal vasomotor symptoms (VMS) significantly impact women’s quality of life, and whilst hormone replacement therapy (HRT) is effective, it is not appropriate for all. We aimed to identify new drug targets for VMS and understand reasons for HRT use through genomic analyses.MethodsIn up to 153,152 women from UK Biobank, a population-based cohort, we performed a genome-wide association study (GWAS) of VMS derived from linked primary-care records and cross-sectional self-reported data. In a subset of this cohort (n=39,356), we analysed exome-sequencing data to test the association of rare deleterious genetic variants with VMS. Finally, we used Mendelian randomisation analysis to investigate the reasons for HRT use and whether these changed over time.FindingsOur GWAS identified a genetic signal near the gene encoding NK3R (TACR3) associated with a lower risk of VMS (OR=0·85 (95% CI 0·82,0·87) per AT allele, P=1·1×10-26), which was consistent with previous studies. However, rare genetic variants predicted to reduce functional NK3R levels were not associated with VMS (P=0·9), though did delay puberty (P=9×10-11). Younger menopause age was causally-associated with greater HRT use before 2002 but not after.InterpretationUsing genomics we demonstrate that changed HRT use since the early 2000s reflects a switch from preventing post-menopausal complications to primarily treating VMS. We provide support for TACR3 in the genetic basis of VMS but unexpectedly find that rare genomic variants predicted to lower NK3R levels did not modify VMS, despite the proven efficacy of NK3R antagonists, suggesting that further biological understanding could benefit therapeutic efficacy.FundingCancer Research UK and UKRI.Research in contextEvidence before the studyIn vivo studies of animal models and clinical studies in humans have determined that menopausal vasomotor symptoms (VMS) result from increased neurokinin B (NKB) signalling via the neurokinin 3 receptor (NK3R) in response to decreased circulating oestradiol levels.Recent Phase II clinical trials have demonstrated the efficacy of NK3R antagonists in reducing VMS.A previous GWAS in 17,695 women identified a genetic signal at the TACR3 locus (which codes for NK3R) as associated with VMS. The locus was also genome-wide significant in a GWAS of oestrogen-replacement use (15,305 cases) derived from self-reported medications in UK Biobank.Added value of this studyThis study represents a novel approach to analysing the rarely captured phenotype of VMS, since few population-based cohorts have asked about menopausal symptoms.To the best of our knowledge, this is the first analyses of VMS identified from linked primary care health records. Literature searches of published papers and codelists have not identified any previous studies of VMS in primary care data. The replication of the known GWAS signal for VMS provides a validation of the coding of this phenotype from primary care data.This is the largest genomic study of VMS currently carried out (92,028 women). Our current analyses are limited by the availability of primary care linked data in ∼45% of the UK Biobank cohort and are based on exome sequencing in 200,000 women. Recently released exome data for the full cohort and further releases of primary care linked data in UK Biobank will allow us to re-visit these analyses further.Implications of all the available evidenceOur analyses of rare coding variation in TACR3 identified an intriguing difference that requires further study; while NK3R antagonist drug treatment reduces VMS, women carrying rare genetic variants resulting in reduced NK3R levels were no less likely to experience VMS.Our genome-wide analyses replicate the genetic signals for VMS at the TACR3 gene locus, however we were unable to unequivocally identify TACR3 as the causal gene at this locus.We suggest that the effect of the common genetic variant on reducing VMS may be through as yet uncharacterised regulatory pathways, and that complete inhibition of NK3R signalling is required to eliminate (rather than reduce) VMS.

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“…The functional effects of antagonist binding kinetics are often examined with insurmountability assays using end-point measurements 37 but also real-time experiments 38 . Although a few studies have paid some attention to the real-time changes in cellular effects 13 , 14 , 39 , 40 , we are the first to report a quantitative analysis method for the real-time cellular responses induced by agonists with antagonist pre-incubations.…”

Section: Discussionmentioning

confidence: 99%

From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action

Nederpelt

Kuzikov

Witte

et al. 2017

Sci Rep

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An important question in drug discovery is how to overcome the significant challenge of high drug attrition rates due to lack of efficacy and safety. A missing link in the understanding of determinants for drug efficacy is the relation between drug-target binding kinetics and signal transduction, particularly in the physiological context of (multiple) endogenous ligands. We hypothesized that the kinetic binding parameters of both drug and endogenous ligand play a crucial role in determining cellular responses, using the NK1 receptor as a model system. We demonstrated that the binding kinetics of both antagonists (DFA and aprepitant) and endogenous agonists (NKA and SP) have significantly different effects on signal transduction profiles, i.e. potency values, in vitro efficacy values and onset rate of signal transduction. The antagonistic effects were most efficacious with slowly dissociating aprepitant and slowly associating NKA while the combination of rapidly dissociating DFA and rapidly associating SP had less significant effects on the signal transduction profiles. These results were consistent throughout different kinetic assays and cellular backgrounds. We conclude that knowledge of the relationship between in vitro drug-target binding kinetics and cellular responses is important to ultimately improve the understanding of drug efficacy in vivo.

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Mapping the binding pocket of a novel, high-affinity, slow dissociating tachykinin NK3 receptor antagonist: Biochemical and electrophysiological characterization

Cited by 7 publications

References 55 publications

Understanding Miltefosine–Membrane Interactions Using Molecular Dynamics Simulations

Understanding Miltefosine–Membrane Interactions Using Molecular Dynamics Simulations

Genomic insights into the mechanism of NK3R antagonists for treatment of menopausal vasomotor symptoms

From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action

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