Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists (original) (raw)
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Journal of computer-aided molecular design, 2002
A neurokinin 2 (NK2) antagonist pharmacophore model has been developed on the basis of five non-peptide antagonists from several structurally diverse classes. To evaluate the pharmacophore model, another 20 antagonists were fitted to the model. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 23 of the 25 antagonists were fitted to the model in a low energy conformation with a low RMS value. The pharmacophore model is described by four pharmacophore elements: Three hydrophobic groups and a hydrogen bond donor represented as a vector. The hydrophobic groups are generally aromatic rings, but this is not a requirement. The antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. The model was able to explain the enantioselectivity of SR48968 and GR159897.
Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance
Cancers
Nowadays, the identification of new therapeutic targets that allow for the development of treatments, which as monotherapy, or in combination with other existing treatments can contribute to improve response rates, prognosis and survival of oncologic patients, is a priority to optimize healthcare within sustainable health systems. Recent studies have demonstrated the role of Substance P (SP) and its preferred receptor, Neurokinin 1 Receptor (NK-1R), in human cancer and the potential antitumor activity of NK-1R antagonists as an anticancer treatment. In this review, we outline the relevant studies published to date regarding the SP/NK-1R complex as a key player in human cancer and also evaluate if the repurposing of already marketed NK-1R antagonists may be useful in the development of new treatment strategies to overcome cancer resistance.
Journal of Molecular Graphics and Modelling, 2010
Protein tyrosine kinases occupy a central position in the control of cellular proliferation and its inactivation might lead to the discovery of a new generation anticancer compounds. Substituted benzothiazoles have been found to mimic the ATP-competitive binding of genistein and quercetin to tyrosine kinase. A series of novel 2-phenyl-1,3-benzothiazoles were synthesized and characterised by IR, 1 H NMR and mass spectroscopy. All the compounds were tested for their anticancer activity against MCF-7 breast cancer cell line with the MTT assay. Most of the compounds showed moderate to good anti-breast cancer activity. Anticancer activity varied with substitution on the benzothiazole nucleus with halogens and at 4 position, substitution of the 2-phenyl moiety with methyl and methoxy groups was also explored. Among the compounds tested with MTT assay, mono fluoro substitution on benzothiazole nucleus and 4-methyl variations at 2-phenyl position demonstrated highest percent growth inhibition of MCF-7 cells. Docking studies of the synthesised compounds was done on EGFR using GRIP batch docking method to study their observed activity.
1-Phenyl-8-azabicyclo[3.2.1]octane ethers: A novel series of neurokinin (NK1) antagonists
Bioorganic & Medicinal Chemistry Letters, 2006
1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK 1 receptor antagonists. Substitution at the 6-exo-position led to high affinity NK 1 antagonists with a prolonged duration of action in vivo. Incorporation of an a-methyl substituent in the pendent benzyl ether side chain gave compounds with increased selectivity over the hERG channel.
Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity
Journal of Medicinal Chemistry, 2021
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Indian Journal of Chemistry -Section B (IJC-B), 2021
The present study describes the synthesis and anticancer evaluation of certain substituted rac-(2S)-2-[(R)-[(4substitutedphenyl){[4-(4-substitutedphenyl)-1,3-thiazol-2-yl]amino}methyl]cyclohexanone derivatives. The in vitro anticancer assay indicating substituted β-amino carbonyl derivatives 4g and 4r are particularly active in both tests (HCT116 and H1299). The 4f, 4o, and 4t are the least functioning; 4m and 4n are marginally active; 4b and 4c are more cytotoxic when the growth inhibition percent is compared with standard drugs Camptothecin (CPT.), Acyclovir (ACV), Cisplatin (CDDP.), Vinblastine (VBL) and Trichothecene (TCT.). Among them, 2-((4-p-tosylthiazol-2-ylamino)(4-hydroxyphenyl)methyl) cyclohexanone 4u exhibits selective cytotoxicities for IC 50 µg/mL against HCT116 and H1299, respectively. Simulation of virtually designed 21 compounds has been studied for active binding sites of Crystal Structure of the Cancer Genomic DNA Mutator APOBEC3B (PDB ID-5CQD) enzyme using molecular modelling of protein-ligand interactions. The in-depth sequencing studies reveal that the involvement of APOBEC3B in cancer mutagenesis. For comparison, the binding behaviour of known standard drugs has also studied. The new SwissADME web utensil that gives free access to a pool of quick yet reliable analytical models is presented for physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry. Among them, in-house capable technique, for example, BOILED-Egg, iLOGP, and Bioavailability Radar, are readily available on the web.
Bioorganic & Medicinal Chemistry Letters, 2012
Steric requirements of binding [Nle 10 ]NKA(4-10) to NK-2 receptor were studied by introducing conformationally constrained amino acid analogs into its sequence. Two series of [Nle 10 ]NKA(4-10) analogs were synthesized to investigate (i) the significance of a putative b-turn in the receptor-ligand interaction by insertion of either (S)-or (R)-Gly 8 {ANC-2}Leu 9 clactams to mimic a b-turn constraint, and (ii) the effect of hindered rotation in the F, v 1 and v 2 dihedral angle space of the crucially important Phe 6 which was replaced systematically with D-Phe, D-and L-Tyr, as well as with their conformationally constrained analogs, Tic, HOTic and b-MePhe. Competition binding experiments with [ 3 H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. The analog possessing only an (R)-Gly 8 {ANC-2}Leu 9 constraint, had the same binding affinity as that of the parent peptide. The rank order of potency of the other analogs showed a cumulative effect of different structural modifications in decreasing the binding affinity, i.e., when changing the configuration of the lactam ring to S, replacing Phe 6 with constrained analogs, Tic or b-MePhe, changing the configuration of the amino acid at position six to D, and introducing a hydroxyl group on the aromatic ring.
Journal of Medicinal Chemistry, 1999
Steric and electrostatic requirements at position 6 of [Nle 10 ]NKA(4-10), a full agonist of NK-2 receptors, for molecular recognition by the receptor were studied. Two series of peptide analogues, (a) p-substituted analogues, [p-X-Phe 6 ,Nle 10 ]NKA(4-10), where X) F, Cl, Br, I, NH 2 , NO 2 , and (b) [D-Phe 6 ,Nle 10 ]NKA(4-10), [Trp 6 ,Nle 10 ]NKA(4-10), and [Chex-Ala 6 ,Nle 10 ]-NKA(4-10), were synthesized, and their biological activity was examined. Competition binding experiments with [ 3 H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. Antagonistic and agonistic properties of the analogues were studied using an in vitro functional assay with hamster tracheal rings. The rank order of potency of agonists was [Nle 10 ]NKA(4-10) ≈ [p-F-Phe 6 ,Nle 10 ]NKA(4-10) > [p-NH 2-Phe 6 ,Nle 10 ]NKA(4-10) > [p-Cl-Phe 6 ,-Nle 10 ]NKA(4-10) > [p-NO 2-Phe 6 ,Nle 10 ]NKA(4-10) > [Trp 6 ,Nle 10 ]NKA(4-10). Size and planarity of the aromatic side chain were crucially important for the biological activity, whereas electrondonating and electron-withdrawing properties of the para-substituent were less important. The results favor the hypothesis that weakly polar π-π interactions exist between the aromatic group and the receptor.
Acyclic NK1 antagonists: Replacements for the benzhydryl group
Bioorganic & Medicinal Chemistry Letters, 1994
An exploration of benzhydryl replacements is described. Whilst bridged and fused polynuclear aromatic systems both incur a reduction in affinity it was possible to replace the benzhydryl by a single phenyl ring with only a modest reduction in affinity. In contrast to the analogous diphenylalanyl ethers the binding was also shown to be stereoselective.