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5-HT1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging : Synthesis, physico-chemical and MR studies
- 2021
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Ingår i: Bioorganic chemistry. - : Elsevier. - 0045-2068. ; 106
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Tidskriftsartikel (refereegranskat)abstract
- Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T-1 or T-2 contrast. This work reports the synthesis and evaluation of 5-HT1A targeted PARACEST MRI contrast agent using 1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide (DO3AM) as the bifunctional chelator, and 5-HT1A-antagonist methoxyphenyl piperazine (MPP) as a targeting unit. The multistep synthesis led to the MPP conjugated DO3AM with 60% yield. CEST-related physicochemical parameters were evaluated after loading DO3AM-MPP with paramagnetic MRI active lanthanides: Gadolinium (Gd-DO3AM-MPP) and Europium (Eu-DO3AM-MPP). Luminescence lifetime measurements with Eu-DO3AM-MPP and computational DFT studies using Gd-DO3AM-MPP revealed the coordination of one water molecule (q = 1.43) with metal-water distance (r(M)-H2O) of 2.7 angstrom and water residence time (tau(m)) of 0.23 ms. The dissociation constant of K-d 62 +/- 0.02 pM as evaluated from fluorescence quenching of 5-HT1A (protein) and docking score of -4.81 in theoretical evaluation reflect the binding potential of the complex Gd-DO3AM-MPP with the receptor 5-HT1A. Insights of the docked pose reflect the importance of NH2 (amide) and aromatic ring in Gd-DO3AM-MPP while interacting with Ser 374 and Phe 370 in the antagonist binding pocket of 5-HT1A. Gd-DO3AM-MPP shows longitudinal relaxivity 5.85 mM(-1)s(-1) with a water residence lifetime of 0.93 ms in hippocampal homogenate containing 5-HT1A. The potentiometric titration of DO3AM-MPP showed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. The in vitro and in vivo studies confirmed the minimal cytotoxicity and presential binding of Gd-DO3AM-MPP with 5-HT1A receptor in the hippocampus region of the mice. Summarizing, the complex Gd-DO3AM-MPP can have a potential for CEST imaging of 5-HT1A receptors.
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| 2. |
- Jha, Preeti, et al.
(författare)
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Insights of ligand binding in modeled h5-HT1A receptor : homology modeling, docking, MM-GBSA, screening and molecular dynamics
- 2022
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Ingår i: Journal of Biomolecular Structure and Dynamics. - : Taylor & Francis. - 0739-1102 .- 1538-0254. ; 40:22, s. 11625-11637
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacologically characterized receptor subtype of the serotonin family, the 5HT1A receptor is implicated in the pathophysiology and treatment of depression and anxiety-related disorders. Being the most extensively targeted receptor for developing novel antidepressants and anxiolytics, a near-ideal theoretical model can aid in high-throughput screening of promising drug candidates. However, the design of potential drug candidates suffers owing to a lack of complete structural information. In this work, homology models of 5-HT1A receptor are generated using two distinct alignments (CW and PSTA) and model building methods (KB and EB). The developed models are validated for virtual screening using a ligand dataset of agonists and antagonists. The best-suited model was efficient in discriminating agonist/antagonist binding. Correlation plots between pKi and docking (R2agonist≥ 0.6, R2antagonist≥ 0.7) and MM-GBSA dG bind values (R2agonist≥ 0.5, R2antagonist≥ 0.7) revealed optimum corroboration between in vitro and in silico outcomes, which further suggested the usefulness of the developed model for the design of high-affinity probes for the neurological disorders.
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| 3. |
- Mishra, Preeti, et al.
(författare)
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Effect of exogenous growth regulators on secondary vascular tissue differentiation in the twigs of Kigelia africana
- 2013
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Ingår i: Phyton - Annales Rei Botanicae. - Horn, Austria : Verlag Berger. - 0079-2047. ; 53:1, s. 133-149
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Tidskriftsartikel (refereegranskat)abstract
- The effect of gibberellic acid (GA), naphthalene acetic acid (NAA) and ethephon on dormant and actively growing twigs of was studied by histological and histochemical staining methods. Application of GA and ethephon alone on dormant twigs did not initiate cambial cell division and differentiation, while application of NAA lead to cambial cell division but failed to differentiate cells towards xylem and phloem. Application of GA together with NAA and the combination of GA, NAA and ethephon induced rapid cambial cell division and differentiation of xylem and phloem elements. In the upper portion of twigs close to the point of GA, NAA and ethephon application the cell walls of cambium and phloem elements underwent lignification, while formation of earlywood and latewood was observed in the lower portion. Moreover the application of this hormone combination on actively growing twigs resulted in the formation of tyloses in vessels and differentiation of parenchyma cells with intercellular spaces towards phloem. The combination of GA-NAA promoted rapid cambial cell division and differentiation towards xylem. Maule’s reaction revealed increase in ‘S’ type of lignin in the walls of newly formed vessels and associated parenchyma cells following GA+NAA treatment.
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| 4. |
- Sirisha, V. L., et al.
(författare)
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Cloning, characterization and impact of up- and down-regulating subabul cinnamyl alcohol dehydrogenase (CAD) gene on plant growth and lignin profiles in transgenic tobacco
- 2011
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Ingår i: Plant growth regulation (Print). - : Springer Nature. - 0167-6903 .- 1573-5087. ; 66:3, s. 239-253
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Tidskriftsartikel (refereegranskat)abstract
- Both cDNA including 5′UTR and 3′UTR and genomic clones of cinnamyl alcohol dehydrogenase (CAD) were isolated and characterized from a pulp-yielding leguminous tree Leucaena leucocephala (LlCAD1). The deduced amino acid sequence shared high identity with orthologous sequences of Acacia mangium × Acacia auriculiformis (83%), Medicago sativa (83%), Nicotiana tabaccum (83%) and Aralia cordata (81%). Full length cDNA contained 78 bases of 5′UTR and 283 bases of 3′UTR, while the genomic clone contained 5 exons and 4 introns. Western blot analysis revealed elevated expression of LlCAD1 in seedling roots and shoots compared to leaves. Sense and antisense CAD tobacco transgenics showed increased and reduced CAD activity accompanied by a change in monomeric lignin composition. Histochemical staining of lignin in down-regulated plants suggested an increase in aldehyde units and a decrease in S/G ratio. Down-regulation of CAD resulted in accumulation of syringic, ferulic, p-coumaric and sinapic acids compared to untransformed controls. These observations were validated by anatomical studies of down-regulated transgenic stems which showed thin walled, elongated phloem and xylem fibres, accompanied by a reduction in the density of vessel elements and amount of secondary xylem when compared to untransformed plants. Furthermore, Klason lignin analysis of CAD antisense transgenics showed 7–32% reduced lignin and normal phenotype as compared to untransformed plants. Such a reduction was not noticed in up-regulated transgenics. These results demonstrate a unique opportunity to explore the significant role that down-regulation of CAD gene plays in reducing lignin content thereby offering potential benefits to the pulp and paper industry.
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| 5. |
- Sivan, Pramod, 1984-, et al.
(författare)
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Occurrence of Reaction xylem in the peduncle of Couroupita Guianensis and Kigelia Pinnata
- 2010
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Ingår i: IAWA Journal. - : Brill. - 0928-1541 .- 2294-1932. ; 31:2, s. 203-216
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Tidskriftsartikel (refereegranskat)abstract
- The anatomy of the secondary xylem and distribution pattern of gelatinous fibres (G-fibres) have been studied in the developing and heavy fruitbearing mature peduncles of Kigelia pinnata and Couroupita guianensis.The peduncle in both the plants developed reaction xylem as a result ofgrowth stresses caused by development of large fruits. In Couroupitapeduncles which are originally horizontal, G-fibre distribution was uni-lateral and similar to that of typical tension wood whereas the hangingKigelia peduncles have uniformly distributed gelatinous fibres throughoutthe xylem. The tension xylem severity was higher in the basal region anddecreased towards the terminal region of the current year’s peduncle butafter fruit development a drastic increase in tension wood severity wasobserved in the terminal region. In the Kigelia peduncles, tension woodseverity in terms of G-layer proportion to lignified wall was found to beless than in Couroupita. The abundance of vessels decreased with highfrequency of gelatinous fibres in Couroupita. The peduncle of Kigelia ischaracterized by high vessel frequency, thin normal fibre walls, and thickouter walls with thin gelatinous layer in tension wood fibres. Dimensionalvariations were also noticed in the mechanical and conducting elementsvarying with tension wood severity.
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