The optical isomers (-)-(S)- and (+)-(R)-3-(2, 6-dimethylphenoxy)-2-methyl-1-propanamine (Me2), h... more The optical isomers (-)-(S)- and (+)-(R)-3-(2, 6-dimethylphenoxy)-2-methyl-1-propanamine (Me2), homologues of the antiarrhythmic and antimyotonic drug mexiletine (Mex), were synthesized and assayed as new potential antimyotonic agents. As observed with Mex, Me2 exhibits an enantioselective behaviour. Tests carried out on sodium currents of single muscle fibres of Rana esculenta demonstrated that (-)-(S)- and (+)-(R)-Me2 were less potent than Mex in producing tonic block, but showed a higher use-dependent block. (-)-(S)-Me2 and (-)-(R)-Mex were also used to study the excitability of muscle fibres of myotonic ADR mice, a phenotype of a recessive form of low G(Cl) myotonia. (-)-(S)-Me2 reduced spontaneous discharges and after discharges better than (-)-(R)-Mex in agreement with the use-dependent block of sodium currents.
The HPLC resolution of a series of racemic alpha-substituted alpha-aryloxy acetic acid methyl est... more The HPLC resolution of a series of racemic alpha-substituted alpha-aryloxy acetic acid methyl esters I on a pi-acid N,N'-(3,5-dinitrobenzoyl)-trans-1,2-diaminocyclohexane as chiral selector was modelled by linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). Our results indicate that the retention process mainly depends on solute lipophilicity and steric properties, whereas enantioselectivity is primarily influenced by electrostatic and steric interactions. CoMFA provided additional information with respect to the LFER study, allowed the mixing of different subsets of I and led to a quantitative 3D model of steric and electrostatic factors responsible for chiral recognition.
2-(p-Chlorophenoxy)isobutyric acid (clofibric acid (1) or CPIB) is a drug known to block chloride... more 2-(p-Chlorophenoxy)isobutyric acid (clofibric acid (1) or CPIB) is a drug known to block chloride membrane conductance (GCl) in rat striated muscle. In the present study chiral analogues of CPIB (2-(p-chlorophenoxy)propionic acid (2) and 2-(p-chlorophenoxy)butyric acid (3)) have been tested to evaluate the influence of chirality on Cl ion flux in the channel. The results showed that the chloride channel conductance strongly depends on the absolute configuration: in fact, the S-(-) isomers of the tested compounds strongly decreased the GCl of skeletal muscle membrane, whereas the R-(+) isomers were virtually ineffective. These data allow the hypothesis that, like other ion channels present in various biological systems, the chloride channel of skeletal muscle membrane could also have a stereospecific binding site (or receptor) regulating chloride ion flux.
The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introdu... more The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARalpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPARalpha and unchanged activity on PPARgamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARgamma and docking experiments in PPARalpha provided a molecular explanation for their different behavior as full and partial agonists of PPARalpha and PPARgamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.
... Citation: Study of the mechanism of action of LT175, a dual PPAR ligand that ameliorates the ... more ... Citation: Study of the mechanism of action of LT175, a dual PPAR ligand that ameliorates the metabolic profile and insulin sensitivity in different mouse models / M. Giudici, F. Gilardi, N. Mitro, F. Loiodice, G. Fracchiolla, A. Laghezza, G. Pochetti, R. Montanari, A. Lavecchia, AC ...
Citation: Analisi dell'attività di un nuovo ligando dei peroxisome proliferator-activated re... more Citation: Analisi dell'attività di un nuovo ligando dei peroxisome proliferator-activated receptors (PPARs)/F. Gilardi, E. Scotti, C. Godio, G. Pochetti, R. Montanari, F. Loiodice, G. Fracchiolla, P. Tortorella, A. Laghezza, A. Lavecchia, E. Novellino, F. Mazza, M. Crestani.(( ...
The optical isomers (-)-(S)- and (+)-(R)-3-(2, 6-dimethylphenoxy)-2-methyl-1-propanamine (Me2), h... more The optical isomers (-)-(S)- and (+)-(R)-3-(2, 6-dimethylphenoxy)-2-methyl-1-propanamine (Me2), homologues of the antiarrhythmic and antimyotonic drug mexiletine (Mex), were synthesized and assayed as new potential antimyotonic agents. As observed with Mex, Me2 exhibits an enantioselective behaviour. Tests carried out on sodium currents of single muscle fibres of Rana esculenta demonstrated that (-)-(S)- and (+)-(R)-Me2 were less potent than Mex in producing tonic block, but showed a higher use-dependent block. (-)-(S)-Me2 and (-)-(R)-Mex were also used to study the excitability of muscle fibres of myotonic ADR mice, a phenotype of a recessive form of low G(Cl) myotonia. (-)-(S)-Me2 reduced spontaneous discharges and after discharges better than (-)-(R)-Mex in agreement with the use-dependent block of sodium currents.
The HPLC resolution of a series of racemic alpha-substituted alpha-aryloxy acetic acid methyl est... more The HPLC resolution of a series of racemic alpha-substituted alpha-aryloxy acetic acid methyl esters I on a pi-acid N,N'-(3,5-dinitrobenzoyl)-trans-1,2-diaminocyclohexane as chiral selector was modelled by linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). Our results indicate that the retention process mainly depends on solute lipophilicity and steric properties, whereas enantioselectivity is primarily influenced by electrostatic and steric interactions. CoMFA provided additional information with respect to the LFER study, allowed the mixing of different subsets of I and led to a quantitative 3D model of steric and electrostatic factors responsible for chiral recognition.
2-(p-Chlorophenoxy)isobutyric acid (clofibric acid (1) or CPIB) is a drug known to block chloride... more 2-(p-Chlorophenoxy)isobutyric acid (clofibric acid (1) or CPIB) is a drug known to block chloride membrane conductance (GCl) in rat striated muscle. In the present study chiral analogues of CPIB (2-(p-chlorophenoxy)propionic acid (2) and 2-(p-chlorophenoxy)butyric acid (3)) have been tested to evaluate the influence of chirality on Cl ion flux in the channel. The results showed that the chloride channel conductance strongly depends on the absolute configuration: in fact, the S-(-) isomers of the tested compounds strongly decreased the GCl of skeletal muscle membrane, whereas the R-(+) isomers were virtually ineffective. These data allow the hypothesis that, like other ion channels present in various biological systems, the chloride channel of skeletal muscle membrane could also have a stereospecific binding site (or receptor) regulating chloride ion flux.
The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introdu... more The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARalpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPARalpha and unchanged activity on PPARgamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARgamma and docking experiments in PPARalpha provided a molecular explanation for their different behavior as full and partial agonists of PPARalpha and PPARgamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.
... Citation: Study of the mechanism of action of LT175, a dual PPAR ligand that ameliorates the ... more ... Citation: Study of the mechanism of action of LT175, a dual PPAR ligand that ameliorates the metabolic profile and insulin sensitivity in different mouse models / M. Giudici, F. Gilardi, N. Mitro, F. Loiodice, G. Fracchiolla, A. Laghezza, G. Pochetti, R. Montanari, A. Lavecchia, AC ...
Citation: Analisi dell'attività di un nuovo ligando dei peroxisome proliferator-activated re... more Citation: Analisi dell'attività di un nuovo ligando dei peroxisome proliferator-activated receptors (PPARs)/F. Gilardi, E. Scotti, C. Godio, G. Pochetti, R. Montanari, F. Loiodice, G. Fracchiolla, P. Tortorella, A. Laghezza, A. Lavecchia, E. Novellino, F. Mazza, M. Crestani.(( ...
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