Application of the bridgehead fragments for the design of conformationally restricted melatonin analogues

Zefirova, O. N.; Baranova, T. Yu.; Ivanova, Anna; Иванов, А. А.; Зефиров, Н. С.

doi:10.1016/j.bioorg.2011.02.002

Cited by 13 publications

(7 citation statements)

References 20 publications

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“…This is due to the peculiar geometry of the ECL2 of rhodopsin, which seals the retinal binding site and prevents the penetration of solvent molecules within the lipophilic binding pocket. As a consequence, in many melatonin receptor models, ECL2 was either deleted or rearranged without a template structure to guide the structural modification [58,62,83]. Probably due to the aforementioned difficulties, structure-based drug design has never been a viable option, as this approach strongly depends on the availability of a reliable receptor structure and of a well-characterized pattern of ligand-receptor interactions.…”

Section: Discussionmentioning

confidence: 99%

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Homology Models of Melatonin Receptors: Challenges and Recent Advances

Pala

Lodola

Bedini

et al. 2013

IJMS

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Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compounds will be commented upon.

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Section: Discussionmentioning

confidence: 99%

“…Zefirova et al first exploited the fully activated form of rhodopsin (PDB ID: 3DQB [82]) to build the agonist-bound form of the MT 2 receptor [83]. Only the TM portions were included in the final MT 2 receptor structure, as loop regions were excluded from the homology modeling procedure.…”

Section: Mt1 and Mt2 Melatonin Receptor Modelsmentioning

confidence: 99%

Homology Models of Melatonin Receptors: Challenges and Recent Advances

Pala

Lodola

Bedini

et al. 2013

IJMS

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“…Unlike some previously reported melatonin restricted analogues, in our case, the rigidity through a secondary amide renders impossible a hydrogen bond. 69,70 This interaction of the amide group with the receptor appears to be relevant at least for the MT 1 subtype. 71 As β-carboline 2 is a partial agonist at both receptors, its ability to activate both MT 1 and MT 2 suggests that the union of 2 to these receptors should occur in an analogous way to that of melatonin.…”

Section: Acs Chemical Neurosciencementioning

confidence: 95%

Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and Melatonin–Pinoline Hybrids

Revenga

Pérez

Morales-García

et al. 2015

ACS Chem. Neurosci.

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6-Methoxy-1,2,3,4-tetrahydro-β-carboline (pinoline) and N-acetyl-5-methoxytryptamine (melatonin) are both structurally related to 5-hydroxytryptamine (serotonin). Here we describe the design, synthesis, and characterization of a series of melatonin rigid analogues resulting from the hybridization of both pinoline and melatonin structures. The pharmacological evaluation of melatonin-pinoline hybrids comprises serotonergic and melatonergic receptors, metabolic enzymes (monoamine oxidases), antioxidant potential, the in vitro blood-brain barrier permeability, and neurogenic studies. Pinoline at trace concentrations and 2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (2) were able to stimulate early neurogenesis and neuronal maturation in an in vitro model of neural stem cells isolated from the adult rat subventricular zone. Such effects are presumably mediated via serotonergic and melatonergic stimulation, respectively.

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“…Molecular modeling was performed using the MT 1 receptor model simulated previously [3] and MODELLER program [11]. The most appropriate model was selected on the basis of moldpf and DOPE scoring functions calculated by MODELLER.…”

Section: N-[(5s)-10-methoxymentioning

confidence: 99%

“…While performing studies on conformationally rigid melatonin analogs, we synthesized a series of indole derivatives fused to bicyclic structures [1][2][3]. Some compounds, including amide I [2], were studied by X-ray analysis [4].…”

mentioning

confidence: 99%

Crystallographic study and molecular modeling on the oxidation product of N-[(8R)-2-methoxy-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepta[b]indol-8-yl]acetamide

et al. 2012

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Crystallization of N- [(8R)-2-methoxy-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepta[b]indol-8-yl]acetamide was accompanied by oxidation at the C 5a -C 10a bond with formation of N- [(5S)-10-methoxy-2,8-dioxo-1,2,3,4,5,6,7,8-octahydro-3,6-methano-1-benzazecin-5-yl]acetamide whose structure was determined by X-ray analysis. Docking of this compound into melatonin-binding pocket of MT 1A receptor was simulated by computer-assisted molecular modeling.While performing studies on conformationally rigid melatonin analogs, we synthesized a series of indole derivatives fused to bicyclic structures [1-3]. Some compounds, including amide I [2], were studied by X-ray analysis [4]. In the present work we made an attempt to perform X-ray analysis of an analog of I containing a methoxy group in the indole fragment. The structure of methoxy derivative II was unambiguously confirmed by NMR, IR, and mass spectra and elemental analysis [2]. However, during preparation of a single crystal of II for X-ray analysis by slow crystallization from a colorless solution in anhydrous CH 2 Cl 2 pale rose crystals separated. The X-ray diffraction data (Fig. 1) allowed us to identify this compound as N- [(5S)-10-methoxy-2,8-dioxo-1,2,3,4,5,6,7,8-octa-hydro-3,6-methano-1-benzazecin-5-yl]acetamide (III) which was formed as a result of oxidative cleavage of the double C 5a -C 10a bond in II (Scheme 1).

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Application of the bridgehead fragments for the design of conformationally restricted melatonin analogues

Cited by 13 publications

References 20 publications

Homology Models of Melatonin Receptors: Challenges and Recent Advances

Homology Models of Melatonin Receptors: Challenges and Recent Advances

Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and Melatonin–Pinoline Hybrids

Crystallographic study and molecular modeling on the oxidation product of N-[(8R)-2-methoxy-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepta[b]indol-8-yl]acetamide

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