Papers by Annamaria Marra
AIM: Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands ... more AIM: Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands for treating different CNS pathologies. Our previous investigations led to identify (R)-RC-33 as a potent and selective S1R agonist.RESULTS: Herein, we report the gram-scale synthesis, pharmacokinetic profile and CNS distribution of (R)-RC-33 in the mouse to determine the most suitable dosage schedule for in vivo administration. For comparative purposes, the same experiments were also performed with PRE-084, the most widely used S1R agonist commonly in pharmacological experiments.DISCUSSION: (R)-RC-33 shows a similar pharmacokinetic profile and a better CNS distribution when compared with PRE-084.CONCLUSION: (R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases.
Bookmarks Related papers MentionsView impact
A rapid and straightforward screening protocol of chiral stationary phases (CSPs) in HPLC and SFC... more A rapid and straightforward screening protocol of chiral stationary phases (CSPs) in HPLC and SFC resulted in three different methods "fit-for-purpose", i.e. analysis and scale-up to semi-preparative enantioselective chromatography. The efficient use of these three methods allowed expedited preparation of an important drug discovery target, (R/S)-1, a potent new sigma 1 (σ1) receptor agonist. The approach taken resulted in significant savings of both time and labor for the isolation of enantiomers compared to the development of a stereo-selective synthesis. The enantiomers of 1 have been isolated allowing studies of their chirooptical properties and an in-deep comparative examination of the pharmacological profile for the individual enantiomers. Copyright © 2015 Elsevier B.V. All rights reserved.
Bookmarks Related papers MentionsView impact
Over the years there has been a growing interest in the therapeutic potential for central nervous... more Over the years there has been a growing interest in the therapeutic potential for central nervous system pathologies of sigma receptor modulators. The widely studied PRE-084 and our compounds RC-33 and RC-34 are very potent and selective sigma 1 receptor agonists that could represent promising drug candidates for Amyotrophic Lateral Sclerosis (ALS). Herein, we develop and validate robust and easy-to-use reverse-phase chromatographic methods suitable for detecting and quantifying PRE-084, RC-33 and RC-34 in mouse blood, brain and spinal cord. An HPLC/UV/ESI-MS system was employed for analyzing PRE-084 and an HPLC/UV-PDA system for determining RC-33 and RC-34. Chromatographic separations were achieved on Waters Symmetry RP18 column (150 × 3.9 mm, 5 µm), eluting with water and acetonitrile (both containing 0.1% formic acid) in gradient conditions. The recovery of PRE-084, RC-33 and RC-34 was >95% in all the considered matrices. Their limits of quantitation and detection were also determined. Validation proved the methods be suitable for separating tested compounds from endogenous interferences, being characterized by good sensitivity, linearity, precision and accuracy. A preliminary central nervous system distribution study showed a high distribution of RC-33 in brain and spinal cord, with concentration values well above the determined limit of quantitation. The proposed methods will be used in future preclinical investigations. Copyright © 2015 John Wiley & Sons, Ltd.Copyright © 2015 John Wiley & Sons, Ltd.
Bookmarks Related papers MentionsView impact
Over the past fifteen years, we reported the design and synthesis of different series of compound... more Over the past fifteen years, we reported the design and synthesis of different series of compounds
targeting the C1 domain of protein kinase C (PKC) that were based on various templates. Out of the
pivalate templates, 2-ij4-IJbenzyloxy)phenyl]-3-hydroxypropyl pivalate (compound 1) emerged as the most
potent and promising PKCα ligand, showing a Ki value of 0.7 μM. In the present contribution our efforts are
aimed at better understanding which structural modifications of the pivalate template are allowed for its
affinity to the C1 domain of PKC to be preserved or increased. To this aim, thirteen novel analogues of
1 were designed and their interaction with the target was evaluated in silico. Designed compounds were
then prepared and fully characterized as well as their affinity for the α and δ isoforms of PKC evaluated.
Additionally, in order to investigate the role of chirality in the ligand–target interaction, the pure
enantiomers of the most interesting PKC ligands were prepared and their affinity for PKC isoforms was
determined. Results from our study revealed that: i) the presence of the ester function seems to be
essential for the ligand–target interaction; ii) only a few structural modifications at the ester group are
allowed for the C1 domain affinity to be preserved; and iii) the [3
H]PDBu replacement experiments showed
that the C1 domain of PKC does not exhibit enantiopreference for the pure stereoisomers of tested
compounds. Altogether our observations provide further insights into the ligand–target interactions of the
PKC C1 domain and represent a step-forward in future development of more specific and effective
PKC ligands.
Bookmarks Related papers MentionsView impact
ABSTRACT In our recent researches racemic RC-33 was identified as a potent and highly promising σ... more ABSTRACT In our recent researches racemic RC-33 was identified as a potent and highly promising σ1 receptor agonist, showing excellent σ1 receptor affinity and promoting the NGF-induced neurite outgrowth in PC12 cell at very low concentrations. Surprisingly, its interaction with the biological target as well as its effect on neurite sprouting were proved to be non-stereoselective. Starting from the observation that an electronegative atom in the scaffold of the molecule is an important pharmacophoric element for the interaction with the receptor counterpart, we hypothesized that the absence of such farmacophoric feature in RC-33 structure could be responsible for the lack of enantioselectivity in the interaction with the target. To verify our hypothesis, in this paper we evaluate- both in silico and in vitro - the ability of a series of enantiomeric arylalkylaminoalcohols and arylpyrrolidinols 1-5, structurally related to RC-33 and all characterized by the presence of an electronegative atom as additional pharmacophore feature, to interact with the σ1 receptor. Interestingly, results of our studies showed that sigma1 receptor exhibits enantiopreference toward compounds characterized by (S)-configuration at the stereogenic center bearing the aromatic moiety only when the alcoholic group at the chiral center is present, thus supporting our original hypothesis.
Bookmarks Related papers MentionsView impact
Chirality, 2013
Bookmarks Related papers MentionsView impact
ChemMedChem, 2013
Bookmarks Related papers MentionsView impact
Bioorganic & Medicinal Chemistry, 2013
Bookmarks Related papers MentionsView impact
Bookmarks Related papers MentionsView impact
Uploads
Papers by Annamaria Marra
targeting the C1 domain of protein kinase C (PKC) that were based on various templates. Out of the
pivalate templates, 2-ij4-IJbenzyloxy)phenyl]-3-hydroxypropyl pivalate (compound 1) emerged as the most
potent and promising PKCα ligand, showing a Ki value of 0.7 μM. In the present contribution our efforts are
aimed at better understanding which structural modifications of the pivalate template are allowed for its
affinity to the C1 domain of PKC to be preserved or increased. To this aim, thirteen novel analogues of
1 were designed and their interaction with the target was evaluated in silico. Designed compounds were
then prepared and fully characterized as well as their affinity for the α and δ isoforms of PKC evaluated.
Additionally, in order to investigate the role of chirality in the ligand–target interaction, the pure
enantiomers of the most interesting PKC ligands were prepared and their affinity for PKC isoforms was
determined. Results from our study revealed that: i) the presence of the ester function seems to be
essential for the ligand–target interaction; ii) only a few structural modifications at the ester group are
allowed for the C1 domain affinity to be preserved; and iii) the [3
H]PDBu replacement experiments showed
that the C1 domain of PKC does not exhibit enantiopreference for the pure stereoisomers of tested
compounds. Altogether our observations provide further insights into the ligand–target interactions of the
PKC C1 domain and represent a step-forward in future development of more specific and effective
PKC ligands.
targeting the C1 domain of protein kinase C (PKC) that were based on various templates. Out of the
pivalate templates, 2-ij4-IJbenzyloxy)phenyl]-3-hydroxypropyl pivalate (compound 1) emerged as the most
potent and promising PKCα ligand, showing a Ki value of 0.7 μM. In the present contribution our efforts are
aimed at better understanding which structural modifications of the pivalate template are allowed for its
affinity to the C1 domain of PKC to be preserved or increased. To this aim, thirteen novel analogues of
1 were designed and their interaction with the target was evaluated in silico. Designed compounds were
then prepared and fully characterized as well as their affinity for the α and δ isoforms of PKC evaluated.
Additionally, in order to investigate the role of chirality in the ligand–target interaction, the pure
enantiomers of the most interesting PKC ligands were prepared and their affinity for PKC isoforms was
determined. Results from our study revealed that: i) the presence of the ester function seems to be
essential for the ligand–target interaction; ii) only a few structural modifications at the ester group are
allowed for the C1 domain affinity to be preserved; and iii) the [3
H]PDBu replacement experiments showed
that the C1 domain of PKC does not exhibit enantiopreference for the pure stereoisomers of tested
compounds. Altogether our observations provide further insights into the ligand–target interactions of the
PKC C1 domain and represent a step-forward in future development of more specific and effective
PKC ligands.