4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabino... more 4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabinoid type-2 receptor (CB2R) ligands. With the aim to improve their physicochemical properties, basically aqueous solubility, two different approaches were followed, entailing the substitution of the alkyl chain with a basic replacement or scaffold modification to 4-hydroxy-2-quinolone structure. According to the first approach, compound 6d was obtained showing slightly reduced receptor affinity (Ki = 60 nM) compared to the lead compound 4 (0.8 nM), but greatly enhanced solubility (400-3400 times depending on the pH of the medium). On the other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone structure enabled the discovery of a novel class of CB2R ligands, such as 7b and 7c, characterized by Ki < 1 nM and selectivity index [SI = Ki(CB1R)/Ki(CB2)] > 1300. At pH 7.4, compound 7c resulted by 100-fold more soluble than 4.
In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudd... more In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol. In HAB rats, acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), with URB694 (0.3 mg/kg), (i) decreased anxiety-like behavior in the elevated plus maze, (ii) increased anandamide levels in the heart, (iii) reduced isoproterenol-induced occurrence of ven...
Amino acid conjugates of lithocholic acid (LCA) have been recently described as effective disrupt... more Amino acid conjugates of lithocholic acid (LCA) have been recently described as effective disruptors of the EphA2-ephrin-A1 interaction able to inhibit EphA2 phosphorylation in intact cells and thus able to block prometastatic responses such as cellular retraction and angiogenesis. However, these LCA-based compounds were significantly more potent at disrupting the EphA2-ephrin-A1 interaction than at blocking phenotype responses in cells, which might reflect an unclear mechanism of action or a metabolic issue responsible for a reduction of the compound concentration at the cell&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s surface. Through the synthesis of new compounds and their examination by a combination of cell-based assays and real-time interaction analysis by surface plasmon resonance, we showed at molecular level that L-tryptophan conjugates of lithocholic acid disrupt EphA2-ephrin-A1 interaction by targeting the EphA 2 receptor and that the presence of a polar group in position 3 of steroid scaffold is a key factor to increase the effective concentration of the compounds in cancer cell lines.
The Eph receptor-ephrin system is an emerging target for the development of novel anti-angiogenic... more The Eph receptor-ephrin system is an emerging target for the development of novel anti-angiogenic therapies. Research programs aimed at developing small-molecule antagonists of the Eph receptors are still in their initial stage as available compounds suffer from pharmacological drawbacks, limiting their application in vitro and in vivo. In the present work, we report the design, synthesis and evaluation of structure-activity relationships of a class of Δ(5)-cholenoyl-amino acid conjugates as Eph-ephrin antagonists. As a major achievement of our exploration, we identified N-(3β-hydroxy-Δ(5)-cholen-24-oyl)-l-tryptophan (UniPR1331) as the first small molecule antagonist of the Eph-ephrin system effective as an anti-angiogenic agent in endothelial cells, bioavailable in mice by the oral route and devoid of biological activity on G protein-coupled and nuclear receptors targeted by bile acid derivatives.
Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclini... more Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD). We previously identified the triazolo-9H-purine, ST1535, as a potent A2A R antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω-1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω-1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A2A R was determined. Two compounds, (2-(3,3-dimethylbutyl)-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-amine (3 b) and 4-(6-amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)-2-methylbutan-2-ol (3 c), exhibited good affinity against A2A R (Ki =0.4 nM and 2 nM, respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).
A liquid chromatographic mass spectrometric assay for the quantification of azithromycin in human... more A liquid chromatographic mass spectrometric assay for the quantification of azithromycin in human plasma was developed. Azithromycin and imipramine (as internal standard, IS) were extracted from 0.5 mL human plasma using extraction with diethyl ether under alkaline conditions. Chromatographic separation of drug and IS was performed using a C18 column at room temperature. A mobile phase consisting of methanol, water, ammonium hydroxide and ammonium acetate was pumped at 0.2 mL/min. The mass spectrometer was operated in positive ion mode and selected ion recording acquisition mode. The ions utilized for quantification of azithromycin and IS were m/z 749.6 (M + H)(+) and m/z 591.4 (fragment) for azithromycin, and 281.1 m/z for internal standard; retention times were 6.9 and 3.4 min, respectively. The calibration curves were linear (r(2) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.999) in the concentration ranges of 10-1000 ng/mL. The mean absolute recoveries for 50 and 500 ng/mL azithromycin and 1 µg/ mL IS were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;75%. The percentage coefficient of variation and mean error were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;11%. Based on validation data, the lower limit of quantification was 10 ng/mL. The present method was successfully applied to determine azithromycin pharmacokinetic parameters in two obese volunteers. The assay had applicability for use in pharmacokinetic studies.
Journal of Chemical Information and Modeling, 2014
The EPH receptor A2 (EPHA2) represents an attractive anticancer target. With the aim to identify ... more The EPH receptor A2 (EPHA2) represents an attractive anticancer target. With the aim to identify novel EPHA2 receptor antagonists, a virtual screening campaign, combining shape-similarity and docking calculations, was conducted on a set of commercially available compounds. A combined score, taking into account both ligand- and structure-based results, was then used to identify the most promising candidates. Two compounds, selected among the best-ranked ones, were identified as EPHA2 receptor antagonists with micromolar affinity.
Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited i... more Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization.
Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by ... more Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by morphine gels, empirically chosen. Aiming to rationalize the selection of the most suitable opioid for the cutaneous delivery, we studied the in vitro penetration through human epidermis of eight opioids, evidencing the critical modifications of the morphinan core. Log P, log D, solid-state features and solubility were determined. Docking simulations were performed using supramolecular assembly made of ceramide VI. The modifications on position 3 of the morphinan core resulted the most relevant in determining both physicochemical characteristics and diffusion pattern. The 3-methoxy group weakened the cohesiveness of the crystal lattice structure and increased the permeation flux (J). Computational studies emphasized that, while permeation is essentially controlled by molecule apolarity, skin retention depends on a fine balance of polar and apolar molecular features. Moreover, ChemPLP scoring the interactions between the opioids and ceramide, correlated with both the amount retained into the epidermis (Qret) and J. The balance of the skin penetration properties and the affinity potency for μ-receptors evidenced hydromorphone as the most suitable compound for the induction of local analgesia.
The second messenger hydrogen peroxide transduces changes in the cellular redox state by reversib... more The second messenger hydrogen peroxide transduces changes in the cellular redox state by reversibly oxidizing protein cysteine residues to sulfenic acid. This signaling event regulates many cellular processes but has never been shown to occur in the brain. Here, we report that hydrogen peroxide heightens endocannabinoid signaling in brain neurons through sulfenylation of cysteines C201 and C208 in monoacylglycerol lipase (MGL), a serine hydrolase that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in nerve terminals. The results suggest that MGL sulfenylation may provide a presynaptic control point for 2-AG-mediated endocannabinoid signaling.
Advances in experimental medicine and biology, 2003
Melatonin (MLT) is known for its radical scavenger activity, which had been related to its abilit... more Melatonin (MLT) is known for its radical scavenger activity, which had been related to its ability to protect neuronal cells from different kinds of oxidative stress. In particular, MLT protects rat cerebellum granular cells from kainate-induced necrosis at concentrations higher than 100 microM, and is able to reduce lipoperoxidation induced by radical stress in rat brain homogenate at similar concentrations. On the other hand, MLT has nanomolar affinity for its membrane receptors (MT1 and MT2), and these are completely saturated at the high concentrations employed when the cytoprotective effect is observed. Other indole derivatives are also known to possess antioxidant and cytoprotective activity. In order to dissociate the cytoprotective effect of MLT from its receptor affinity, and to investigate the structure-activity relationships (SAR) between this effect and some potentially relevant chemical properties, we prepared a series of indole derivatives, where the structure of MLT w...
Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to ... more Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.
4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabino... more 4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabinoid type-2 receptor (CB2R) ligands. With the aim to improve their physicochemical properties, basically aqueous solubility, two different approaches were followed, entailing the substitution of the alkyl chain with a basic replacement or scaffold modification to 4-hydroxy-2-quinolone structure. According to the first approach, compound 6d was obtained showing slightly reduced receptor affinity (Ki = 60 nM) compared to the lead compound 4 (0.8 nM), but greatly enhanced solubility (400-3400 times depending on the pH of the medium). On the other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone structure enabled the discovery of a novel class of CB2R ligands, such as 7b and 7c, characterized by Ki < 1 nM and selectivity index [SI = Ki(CB1R)/Ki(CB2)] > 1300. At pH 7.4, compound 7c resulted by 100-fold more soluble than 4.
In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudd... more In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol. In HAB rats, acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), with URB694 (0.3 mg/kg), (i) decreased anxiety-like behavior in the elevated plus maze, (ii) increased anandamide levels in the heart, (iii) reduced isoproterenol-induced occurrence of ven...
Amino acid conjugates of lithocholic acid (LCA) have been recently described as effective disrupt... more Amino acid conjugates of lithocholic acid (LCA) have been recently described as effective disruptors of the EphA2-ephrin-A1 interaction able to inhibit EphA2 phosphorylation in intact cells and thus able to block prometastatic responses such as cellular retraction and angiogenesis. However, these LCA-based compounds were significantly more potent at disrupting the EphA2-ephrin-A1 interaction than at blocking phenotype responses in cells, which might reflect an unclear mechanism of action or a metabolic issue responsible for a reduction of the compound concentration at the cell&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s surface. Through the synthesis of new compounds and their examination by a combination of cell-based assays and real-time interaction analysis by surface plasmon resonance, we showed at molecular level that L-tryptophan conjugates of lithocholic acid disrupt EphA2-ephrin-A1 interaction by targeting the EphA 2 receptor and that the presence of a polar group in position 3 of steroid scaffold is a key factor to increase the effective concentration of the compounds in cancer cell lines.
The Eph receptor-ephrin system is an emerging target for the development of novel anti-angiogenic... more The Eph receptor-ephrin system is an emerging target for the development of novel anti-angiogenic therapies. Research programs aimed at developing small-molecule antagonists of the Eph receptors are still in their initial stage as available compounds suffer from pharmacological drawbacks, limiting their application in vitro and in vivo. In the present work, we report the design, synthesis and evaluation of structure-activity relationships of a class of Δ(5)-cholenoyl-amino acid conjugates as Eph-ephrin antagonists. As a major achievement of our exploration, we identified N-(3β-hydroxy-Δ(5)-cholen-24-oyl)-l-tryptophan (UniPR1331) as the first small molecule antagonist of the Eph-ephrin system effective as an anti-angiogenic agent in endothelial cells, bioavailable in mice by the oral route and devoid of biological activity on G protein-coupled and nuclear receptors targeted by bile acid derivatives.
Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclini... more Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD). We previously identified the triazolo-9H-purine, ST1535, as a potent A2A R antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω-1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω-1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A2A R was determined. Two compounds, (2-(3,3-dimethylbutyl)-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-amine (3 b) and 4-(6-amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)-2-methylbutan-2-ol (3 c), exhibited good affinity against A2A R (Ki =0.4 nM and 2 nM, respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).
A liquid chromatographic mass spectrometric assay for the quantification of azithromycin in human... more A liquid chromatographic mass spectrometric assay for the quantification of azithromycin in human plasma was developed. Azithromycin and imipramine (as internal standard, IS) were extracted from 0.5 mL human plasma using extraction with diethyl ether under alkaline conditions. Chromatographic separation of drug and IS was performed using a C18 column at room temperature. A mobile phase consisting of methanol, water, ammonium hydroxide and ammonium acetate was pumped at 0.2 mL/min. The mass spectrometer was operated in positive ion mode and selected ion recording acquisition mode. The ions utilized for quantification of azithromycin and IS were m/z 749.6 (M + H)(+) and m/z 591.4 (fragment) for azithromycin, and 281.1 m/z for internal standard; retention times were 6.9 and 3.4 min, respectively. The calibration curves were linear (r(2) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.999) in the concentration ranges of 10-1000 ng/mL. The mean absolute recoveries for 50 and 500 ng/mL azithromycin and 1 µg/ mL IS were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;75%. The percentage coefficient of variation and mean error were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;11%. Based on validation data, the lower limit of quantification was 10 ng/mL. The present method was successfully applied to determine azithromycin pharmacokinetic parameters in two obese volunteers. The assay had applicability for use in pharmacokinetic studies.
Journal of Chemical Information and Modeling, 2014
The EPH receptor A2 (EPHA2) represents an attractive anticancer target. With the aim to identify ... more The EPH receptor A2 (EPHA2) represents an attractive anticancer target. With the aim to identify novel EPHA2 receptor antagonists, a virtual screening campaign, combining shape-similarity and docking calculations, was conducted on a set of commercially available compounds. A combined score, taking into account both ligand- and structure-based results, was then used to identify the most promising candidates. Two compounds, selected among the best-ranked ones, were identified as EPHA2 receptor antagonists with micromolar affinity.
Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited i... more Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization.
Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by ... more Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by morphine gels, empirically chosen. Aiming to rationalize the selection of the most suitable opioid for the cutaneous delivery, we studied the in vitro penetration through human epidermis of eight opioids, evidencing the critical modifications of the morphinan core. Log P, log D, solid-state features and solubility were determined. Docking simulations were performed using supramolecular assembly made of ceramide VI. The modifications on position 3 of the morphinan core resulted the most relevant in determining both physicochemical characteristics and diffusion pattern. The 3-methoxy group weakened the cohesiveness of the crystal lattice structure and increased the permeation flux (J). Computational studies emphasized that, while permeation is essentially controlled by molecule apolarity, skin retention depends on a fine balance of polar and apolar molecular features. Moreover, ChemPLP scoring the interactions between the opioids and ceramide, correlated with both the amount retained into the epidermis (Qret) and J. The balance of the skin penetration properties and the affinity potency for μ-receptors evidenced hydromorphone as the most suitable compound for the induction of local analgesia.
The second messenger hydrogen peroxide transduces changes in the cellular redox state by reversib... more The second messenger hydrogen peroxide transduces changes in the cellular redox state by reversibly oxidizing protein cysteine residues to sulfenic acid. This signaling event regulates many cellular processes but has never been shown to occur in the brain. Here, we report that hydrogen peroxide heightens endocannabinoid signaling in brain neurons through sulfenylation of cysteines C201 and C208 in monoacylglycerol lipase (MGL), a serine hydrolase that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in nerve terminals. The results suggest that MGL sulfenylation may provide a presynaptic control point for 2-AG-mediated endocannabinoid signaling.
Advances in experimental medicine and biology, 2003
Melatonin (MLT) is known for its radical scavenger activity, which had been related to its abilit... more Melatonin (MLT) is known for its radical scavenger activity, which had been related to its ability to protect neuronal cells from different kinds of oxidative stress. In particular, MLT protects rat cerebellum granular cells from kainate-induced necrosis at concentrations higher than 100 microM, and is able to reduce lipoperoxidation induced by radical stress in rat brain homogenate at similar concentrations. On the other hand, MLT has nanomolar affinity for its membrane receptors (MT1 and MT2), and these are completely saturated at the high concentrations employed when the cytoprotective effect is observed. Other indole derivatives are also known to possess antioxidant and cytoprotective activity. In order to dissociate the cytoprotective effect of MLT from its receptor affinity, and to investigate the structure-activity relationships (SAR) between this effect and some potentially relevant chemical properties, we prepared a series of indole derivatives, where the structure of MLT w...
Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to ... more Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.
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Papers by Federica Vacondio