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Dive into the research topics where Maria Pigini is active.

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Featured researches published by Maria Pigini.


Bioorganic & Medicinal Chemistry | 1997

Imidazoline receptors: Qualitative structure-activity relationships and discovery of tracizoline and benazoline. Two ligands with high affinity and unprecedented selectivity☆

Maria Pigini; Pascal Bousquet; Angelo Carotti; M. Dontenwill; Mario Giannella; Roberta Moriconi; Alessandro Piergentili; Wilma Quaglia; Seyed Khosrow Tayebati; Livio Brasili

The observation that all the attempts to characterize imidazoline (I) receptors have been carried out with non-selective or poorly selective ligands prompted us to undertaken research aimed at developing selective ligand(s). In previous work using, as a starting point, cirazoline I, a potent alpha 1-adrenergic receptor agonist that also binds to I receptors, we showed that removal of the cyclopropyl ring (2) retains high affinity for I2 receptors while reducing alpha 1-adrenergic agonist activity. However, it was felt that this residual, albeit modest, alpha 1-adrenergic agonist activity might diminish the usefulness of compound 2, and we now report on our continuing efforts in this field. Starting from compound 2, we first eliminated the alpha 1-agonist component by isosteric replacement and then, by means of conformational restrictions on compound 7, succeeded in discovering tracizoline (9) and benazoline (12). These two new ligands with high affinity (pKi value 8.74 and 9.07, respectively) and unprecedented selectivity with respect to both alpha 2- (I2/alpha 2 7,762 and 18,621) and alpha 1- (I2/alpha 1 2,344 and 2,691) adrenergic receptors, are valuable tools in the study of I receptor structure and function. In addition, the large number of derivatives studied has allowed us to establish congruent qualitative structure-activity relationships and identify some structural elements governing affinity and selectivity.


Current Topics in Medicinal Chemistry | 2007

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

Francesco Gentili; Maria Pigini; Alessandro Piergentili; Mario Giannella

Chemical and biological strategies have provided evidence for alpha(2)-receptor heterogeneity, to date classified in three different subtypes, alpha(2A), alpha(2B), and alpha(2C). These are widely distributed throughout the body and mediate numerous effects; therefore, the potential therapeutic indications of agonists and antagonists are numerous. Nevertheless, the lack of subtype-selectivity of the well-known compounds represents a major limit for their use. SAR studies may help to design new and more selective drugs.


European Journal of Pharmacology | 2000

Hyperphagic effect of novel compounds with high affinity for imidazoline I2 binding sites

Carlo Polidori; Francesco Gentili; Maria Pigini; Wilma Quaglia; Izabela Panocka; Maurizio Massi

Previous studies have suggested that imidazoline I(2) receptors play a role in feeding control in rats. The effect of subcutaneous (s.c.) injections of four novel imidazoline I(2) ligands, 2-naphthalen-2yl-4,5-dihydro-1H-imidazole hydrochloride (benazoline), 2-styryl-4,5-dihydro-1H-imidazole oxalate (tracizoline), o-nitro-tracizoline and o-methyl-tracizoline (metrazoline) on food intake during the light phase was now evaluated in freely feeding male Wistar rats. Their effect was compared to that of idazoxan, a high-affinity ligand at imidazoline I(2) binding sites, but also a potent alpha(2)-adrenoceptor antagonist. Compared to idazoxan, metrazoline exhibits a higher pK(i) for imidazoline I(2) binding sites in rat liver, while the other compounds have a slightly lower pK(i); on the other hand, the novel compounds have much lower affinity than idazoxan at alpha(2)-adrenoceptors. Idazoxan stimulated drinking at a dose as low as 1 mg/kg, and evoked feeding at a higher dose (30 mg/kg). The selective alpha(2)-adrenoceptor antagonist 2-methoxy-idazoxan (RX821002), with negligible affinity at imidazoline I(2) binding sites, significantly increased drinking but failed to stimulate feeding at doses of 10-50 mg/kg. Metrazoline induced hyperphagia and water drinking at doses of 50 mg/kg or higher. Its dipsogenic effect was secondary to the hyperphagic effect, since it was not observed in rats without access to food. Benazoline significantly increased feeding only in response to 30 mg/kg, but its effect was less pronounced than that of metrazoline. Tracizoline and o-nitro-tracizoline were inactive. Following injection into the lateral cerebroventricle at doses up to 100 microgram/rat, and into the third or fourth brain ventricle at doses up to 50 microgram/rat, neither idazoxan nor metrazoline induced hyperphagia. The present results support the idea that imidazoline I(2) ligands influence feeding in rats, and suggest that their site of action is not in the central nervous system. The finding that idazoxan elicits a more potent hyperphagic effect than metrazoline and benazoline, although its affinity for imidazoline I(2) binding sites is lower than that of metrazoline and similar to that of benazoline, raises the question whether its hyperphagic effect might also be due to interaction with other receptors.


British Journal of Pharmacology | 2012

Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats

David A. Thorn; Xiao-Fei An; Yanan Zhang; Maria Pigini; Jun-Xu Li

BACKGROUND AND PURPOSE Imidazoline I2 receptors have been implicated in several CNS disorders. Although several I2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I2 receptor ligands. This study examined I2 receptor agonist‐induced hypothermia as a functional in vivo assay of I2 receptor agonism.


Journal of Medicinal Chemistry | 2008

Α2-Adrenoreceptors Profile Modulation. 4.1 From Antagonist to Agonist Behavior

Francesco Gentili; Claudia Cardinaletti; Cristian Vesprini; Antonio Carrieri; Francesca Ghelfi; A. Farande; Mario Giannella; Alessandro Piergentili; Wilma Quaglia; Jonne M. Laurila; Anna Huhtinen; Mika Scheinin; Maria Pigini

The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors.


Bioorganic & Medicinal Chemistry | 1997

2-D and 3-D modeling of imidazoline receptor ligands: Insights into pharmacophore

Antonio Carrieri; Livio Brasili; Francesco Leonetti; Maria Pigini; Mario Giannella; Pascal Bousquet; Angelo Carotti

A 3-D quantitative structure-activity relationship (3-D QSAR) study was carried out using comparative molecular field analysis (CoMFA) on both imidazoline (I2R) and alpha 2 receptor binding affinities of a large series of 2-substituted imidazolines. Significant cross-validated correlations, having promising predictive ability, were obtained along with 3-D pharmacophore models that defined the spatial regions where steric and electrostatic interactions may modulate the in vitro binding affinities and indicated possible physicochemical and structural requirements for I2/alpha 2 receptor selectivity.


Bioorganic & Medicinal Chemistry | 2012

Favourable involvement of α2A-adrenoreceptor antagonism in the I₂-imidazoline binding sites-mediated morphine analgesia enhancement.

Valerio Mammoli; Alessandro Bonifazi; Fabio Del Bello; Eleonora Diamanti; Mario Giannella; Alan L. Hudson; Laura Mattioli; Marina Perfumi; Alessandro Piergentili; Wilma Quaglia; Federica Titomanlio; Maria Pigini

Aim of the present study was to obtain novel α(2)-adrenoreceptor (α(2)-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α(2)-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole α(2A)-subtype. Moreover, 2 showed an affinity at I(2)-imidazoline binding sites (I(2)-IBS) comparable to that at α(2A)-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α(2A)-AR antagonism in the I(2)-IBS-mediated morphine analgesia enhancement.


Journal of Medicinal Chemistry | 2010

Fruitful Adrenergic α2C-Agonism/α2A-Antagonism Combination to Prevent and Contrast Morphine Tolerance and Dependence(1),†

Fabio Del Bello; Laura Mattioli; Francesca Ghelfi; Mario Giannella; Alessandro Piergentili; Wilma Quaglia; Claudia Cardinaletti; Marina Perfumi; Russell J. Thomas; Ugo Zanelli; Carla Marchioro; Michele Dal Cin; Maria Pigini

The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; the corresponding distomers are partial agonists. Because in clinical pain management with opioids α(2C)-AR agonists, devoid of the α(2A)-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing α(2C)-agonism/α(2A)-antagonism, have been studied in vivo. The data suggest that partial α(2C)-activation is compatible with effective enhancement of morphine analgesia and reduction both of morphine tolerance acquisition and morphine dependence acquisition and expression. On the contrary, full α(2C)-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(+)-4 has been found to be very unusual.


Bioorganic & Medicinal Chemistry | 1998

Ligand binding to I2 imidazoline receptor: the role of lipophilicity in quantitative structure-activity relationship models.

Maria Pigini; Pascal Bousquet; Livio Brasili; Antonio Carrieri; R. Cavagna; M. Dontenwill; Francesco Gentili; Mario Giannella; Francesco Leonetti; Alessandro Piergentili; Wilma Quaglia; Angelo Carotti

A series of 2-trans-styryl-imidazoline (tracizoline) congeners were designed and tested to develop 2-D and 3-D QSAR models for their binding to imidazoline (I2) receptor. The important role of lipophilicity was assessed by classical 2-D QSAR study (Hansch approach) and by comparative molecular field analysis (CoMFA) with the inclusion of the molecular lipophilicity potential (MLP), as an additional descriptor, besides standard steric and electrostatic fields. Results from these studies were compared to those obtained in a previous modeling study of I2 receptor ligands and integrated into a new, comprehensive model, based on about sixty I2 receptor ligands. This model revealed, at the three-dimensional level, the most significant steric, electrostatic, and lipophilic interactions accounting for high I2 receptor affinity.


Journal of Medicinal Chemistry | 2010

Novel Highly Potent and Selective σ1 Receptor Antagonists Related to Spipethiane

Alessandro Piergentili; Consuelo Amantini; Fabio Del Bello; Mario Giannella; Laura Mattioli; Maura Palmery; Marina Perfumi; Maria Pigini; Giorgio Santoni; Paolo Tucci; Margherita Zotti; Wilma Quaglia

Conservative chemical modifications of the core structure of the lead spipethiane (1) afforded novel potent sigma(1) ligands. sigma(1) affinity and sigma(1/)sigma(2) selectivity proved to be favored by the introduction of polar functions (oxygen atom or carbonyl group) in position 3 or 4 (4-6) or by the elongation of the distance between the two hydrophobic portions of the molecule with the simultaneous presence of a carbonyl group in position 4 (8 and 9). The observed cytostatic effect against the human breast cancer cell line MCF-7/ADR, highly expressing sigma(1) receptors, and not against MCF-7, as well as the enhancement of morphine analgesia highlighted the sigma(1) antagonist profile of this series of compounds. In particular, due to its high sigma(1) affinity (pK(i) = 10.28) and sigma(1)/sigma(2) selectivity ratio (29510), compound 9 might be a novel valuable tool for sigma receptor characterization and a suitable template for the rational design of potential therapeutically useful sigma(1) antagonists.

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Livio Brasili

University of Modena and Reggio Emilia

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