Abstract Riboflavin (RF) is an essential water-soluble vitamin with unique biological and physicochemical properties such as transporterspecific cell internalization, implication in redox reactions, ...fluorescence and photosensitizing. Due to these features RF attracted researchers in various fields from targeted drug delivery and tissue engineering to optoelectronics and biosensors. In this review we will give a brief reminder of RF chemistry, its optical, photosensitizing properties, RF transporter systems and its role in pathologies. We will point a special attention on the recent findings concerning RF applications in nanotechnologies such as RF functionalized nanoparticles, polymers, biomolecules, carbon nanotubes, hydrogels and implants for tissue engineering.
For the development of novel 5-HT(4) receptor ligands we have designed and synthesized two series of 5-methoxytryptamine derivatives varying the substitution on the primary amine. Their biological ...activities were evaluated in a receptor binding assay where a subset of compounds showed comparable potency to the agonists serotonin and 5-methoxytryptamine. Structure-activity analyses have highlighted promising avenues for further synthetic work and binding modes were proposed by docking these compounds into a homology model of the 5-HT(4) receptor.
A series of 30 tripeptides were synthesized and tested as novel 5-HT4 receptor ligands. Receptor binding assays showed that a subset of compounds had reasonable potency relative to the agonists ...serotonin and 5-methoxytryptamine. Structure-activity analyses and molecular docking have highlighted avenues for further synthetic work.
Photoacoustic imaging is an emerging method in the molecular imaging field, providing high spatiotemporal resolution and sufficient imaging depths for many clinical applications. Therefore, the aim ...of this study was to use photoacoustic imaging as a tool to evaluate a riboflavin (RF)-based targeted nanoplatform. RF is internalized by the cells through a specific pathway, and its derivatives were recently shown as promising tumor-targeting vectors for the drug delivery systems. Here, the RF amphiphile synthesized from a PEGylated phospholipid was successfully inserted into a long-circulating liposome formulation labeled with the clinically approved photoacoustic contrast agent - indocyanine green (ICG). The obtained liposomes had a diameter of 124 nm (polydispersity index =0.17) and had a negative zeta potential of -26 mV. Studies in biological phantoms indicated a stable and concentration-dependent photoacoustic signal (Vevo
LAZR) of the ICG-containing RF-functionalized liposomes. In A431 cells, a high uptake of RF-functionalized liposomes was found and could be blocked competitively. First, studies in mice revealed ~3 times higher photoacoustic signal in subcutaneous A431 tumor xenografts (
<0.05) after injection of RF-functionalized liposomes compared to control particles. In this context, the application of a spectral unmixing protocol confirmed the initial quantitative data and improved the localization of liposomes in the tumor. In conclusion, the synthesized RF amphiphile leads to efficient liposomal tumor targeting and can be favorably detected by photoacoustic imaging with a perspective of theranostic applications.
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► Combined Supramolecular Systems were formed via interactions of two Nucleoside–Lipids. ► These systems feature new macroscopic properties due to lipid polar head interactions. ► ...This approach is of interest for supramolecular engineering.
We report the synthesis of a new series of Ketal Nucleoside Lipids (KNLs) featuring saturated hydrophobic double chains and either adenosine or uridine as nucleosides (KNLA and KNLU, respectively). Physicochemical studies (differential scanning calorimetry, small angle X ray scattering, transmission electronic microscopy, atomic force microscopy, Langmuir isotherm, infrared spectroscopy) show that the KNLs form hydrogels below the main phase transition temperature (Tm), whereas fluid lamellar phases are obtained above Tm. Mixing complementary KNLs affords a new stable Combined Supramolecular Systems (CSSs) due to complementary A-U recognition. Molecular modeling calculations of the bilayers in a fluid state exhibit a merging of the bilayers partially due to base–base interactions.
Supramolecular assembly formation resulting from molecular recognition between complementary nucleolipids has been visualized in real time at the micrometer scale.
RT–PCR technique was used to clone the human 5‐HT4(e) receptor (h5‐HT4(e)) from heart atrium. We showed that this h5‐HT4(e) receptor splice variant is restricted to brain and heart atrium.
...Recombinant h5‐HT4(e) receptor was stably expressed in CHO and C6‐glial cell lines at 347 and 88 fmol mg−1 protein, respectively. Expression of h5‐HT4(e) receptors at the cell membrane was confirmed by immunoblotting.
The receptor binding profile, determined by competition with 3H‐GR113808 of a number of 5‐HT4 ligands, was consistent with that previously reported for other 5‐HT4 receptor isoforms. Surprisingly, we found that the rank order of potencies (EC50) of 5‐HT4 agonists obtained from adenylyl cyclase functional assays was inversely correlated to their rank order of affinities (Ki) obtained from binding assays. Furthermore, EC50 values for 5‐HT, renzapride and cisapride were 2 fold lower in C6‐glial cells than in CHO cells.
ML10302 and renzapride behaved like partial agonists on the h5‐HT4(e) receptor. These results are in agreement with the reported low efficacy of the these two compounds on L‐type Ca2+ currents and myocyte contractility in human atrium.
A constitutive activity of the h5‐HT4(e) receptor was observed in CHO cells in the absence of any 5‐HT4 ligand and two 5‐HT4 antagonists, GR113808 and ML10375, behaved as inverse agonists.
These data show that the h5‐HT4(e) receptor has a pharmacological profile which is close to the native h5‐HT4 receptor in human atrium with a functional potency which is dependent on the cellular context in which the receptor is expressed.
British Journal of Pharmacology (2000) 129, 771–781; doi:10.1038/sj.bjp.0703101
Among the five human 5‐HT4 (h5‐HT4) receptor isoforms, the h5‐HT4(a) receptor was studied with a particular emphasis on the molecular interactions involved in ligand binding. For this purpose, we ...used site‐directed mutagenesis of the transmembrane domain. Twelve mutants were constructed with a special focus on the residue P4.53 of helix IV which substitutes in h5‐HT4 receptors the highly conserved S residue among the rhodopsin family receptors. The mutated receptors were transiently expressed in COS‐7 cells.
Ligand binding or competition studies with two h5‐HT4 receptor agonists, serotonin and ML10302 and two h5‐HT4 receptor antagonists, 3H‐GR113808 and ML10375 were performed on wild type and mutant receptors. Functional activity of the receptors was evaluated by measuring the ability of serotonin to stimulate adenylyl cyclase.
Ligand binding experiments revealed that 3H‐GR113808 did not bind to mutants P4.53A, S5.43A, F6.51A, Y7.43A and to double mutant F6.52V/N6.55L. On the other hand mutations D3.32N, S5.43A and Y7.43A appeared to promote a dramatic decrease of h5‐HT4(a) receptor functional activity. From these studies, S5.43 and Y7.43 clearly emerged as common anchoring sites to antagonist 3H‐GR113808 and to serotonin.
According to these results, we propose ligand‐receptor complex models with serotonin and 3H‐GR113808. For serotonin, three interaction points were selected including ionic interaction with D3.32, a stabilizing interaction of this ion pair by Y7.43 and a hydrogen bond with S5.43. 3H‐GR113808 was also docked, based on the same type of interactions with S5.43 and D3.32: the proposed model suggested a possible role of P4.53 in helix IV structure allowing the involvement of a close hydrophobic residue, W4.50, in a hydrophobic pocket for hydrophobic interactions with the indole ring of 3H‐GR113808.
British Journal of Pharmacology (2000) 130, 527–538; doi:10.1038/sj.bjp.0703356
Classical antidepressants are thought to act by raising monoamine (serotonin and noradrenaline) levels in the brain. This action is generally accomplished either by inhibition of monoamine metabolism ...(MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer from a time lag (3−6 weeks) before robust clinical efficacy can be demonstrated. This delay may reflect inhibitory actions of noradrenaline at presynaptic α2A-adrenergic auto- or heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presynaptic α2A-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature, only two molecules have been described with such a pharmacological profile. Of these, napamezole (2) was chosen as a point of departure for the design of 4(5)-(3,4-dihydro-2-naphthalenyl)methyl-4,5-dihydroimidazole (4a), which displayed the desired profile: α2A-adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this original molecule, a series of derivatives was designed and synthesized, encompassing substituted as well as rigid analogues. Structure−activity relationships permitted the selection of 14c (4(5)-(5-fluoroindan-2-yl)methyl-4,5-dihydroimidazole) as a development candidate.
Classical antidepressants are thought to act by raising monoamine (serotonin and noradrenaline) levels in the brain. This action is generally accomplished either by inhibition of monoamine metabolism ...(MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer from a time lag (3--6 weeks) before robust clinical efficacy can be demonstrated. This delay may reflect inhibitory actions of noradrenaline at presynaptic alpha(2A)-adrenergic auto- or heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presynaptic alpha(2A)-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature, only two molecules have been described with such a pharmacological profile. Of these, napamezole (2) was chosen as a point of departure for the design of 4(5)-(3,4-dihydro-2-naphthalenyl)methyl-4,5-dihydroimidazole (4a), which displayed the desired profile: alpha(2A)-adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this original molecule, a series of derivatives was designed and synthesized, encompassing substituted as well as rigid analogues. Structure-activity relationships permitted the selection of 14c (4(5)-(5-fluoroindan-2-yl)methyl-4,5-dihydroimidazole) as a development candidate.
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