Whole body vibration and treadmill training in Parkinson's disease rehabilitation: effects on energy cost and recovery phases.

BACKGROUND: Although physical treatment is recognized as being beneficial for patients with Parkinson's disease (PD), there is scant literature on the type of rehabilitation program most useful for patients with PD. The aim of the present study was to investigate the effects of two different training protocols (aerobic treadmill training, AER and whole body vibration training, WBVT) on energy cost and adaptations after exercise and recovery phases, by means of the oxygen consumption measurement and the assay of metabolic biochemical substrates. METHODS: Twenty male patients with idiopathic Parkinson's disease, aged 51-66 years, were enrolled. Patients were randomly assigned to the training groups. The total work time was 20 min per group for 4 weeks, four times a week. In both groups, training intensity was monitored by the ratings of perceived exertion (RPE). Workload was gradually increased until patients worked up to the exertion level of 13 to 15 on the 20-point Borg scale RPE. The outcome measures were oxygen consumption, free fatty acid (FFA), and amino acid (AA) levels. RESULTS: The oxygen consumption during exercises does not show significant differences between the two training groups. Instead, only in the AER group, excess post-exercise oxygen consumption measurements increased significantly (p < 0.01) as well as FFA availability (p < 0.01). CONCLUSION: The WBVT does not appear to require a long time of recovery and leads to less feeling of fatigue, whereas AER needs an appropriate recovery time after the training session.

QSAR studies on BK channel activators.

QSAR studies were developed on the basis of a dataset comprising BK channel activators previously synthesized and biologically assayed in our laboratory, in order to obtain highly accurate models enabling prediction of affinity toward the channel for New Chemical Entities (NCEs). Many molecular descriptors were computed by the CODESSA software. They were initially exploited in order to rationally split the available dataset into training and test set pairs, which supplied the basis for the development of QSAR models. Models were subjected to rigorous validation analysis based on the estimate of several statistical parameters, for the seek of the most accurate and simplest model enabling prediction of BK channel affinity.

1,2,3-Triazol-carboxanilides and 1,2,3-triazol-(N-benzyl)-carboxamides as BK-potassium channel activators. XII.

The chemical structures of many synthetic activators of large-conductance calcium-activated potassium channels (BK channels) satisfy a simple pharmacophore model, consisting of two appropriately substituted phenyl rings connected by a linker of a heterogeneous nature. In this paper, a series of new compounds with modifications of the linker portion of the above pharmacophore are described. In particular, in these new derivatives, the linker portion is represented by a 1,2,3-triazole-carboxamide group, which can be viewed as a combination of two different kinds of linker, independently used in previous series of BK-openers: the amide function and the 1,2,3-triazole ring. The overall finding of this study indicated that the triazole-carboxamide derivatives were generally poorly effective and that this structural modification of the linker is deleterious for activity on BK channels. Therefore, it can be hypothesized that the increase of the steric hindrance of the linker and/or the increase of the distance between the two aromatic portions are negative for the interaction with the biological target.

New amido derivatives as potential BKCa potassium channel activators. XI.

The vasorelaxing effects of exogenous activators of large-conductance calcium-activated potassium channels (BK channels) can furnish the pharmacological rational basis for the treatment of hypertension and/or other diseases related with an impaired contractility of vessels. Since in previous works some benzanilide derivatives showed BK channel-induced vasorelaxing activity, in this paper we have taken into consideration the introduction of methylene spacer(s) between the amide linker and one or both the aromatic substituents, to evaluate the pharmacological effect caused by these lengthenings and to obtain possible useful information about structure-activity relationships. Overall, the main findings of this work suggest that the introduction of one or two methylene group(s) in the amide linker exerts a negative influence on the BK-opening properties, which can be due to an excessive lengthening of the spacer between the two aromatic rings and/or to further degrees of conformational freedom.

Synthesis, biological activity and molecular modelling of new trisubstituted 8-azaadenines with high affinity for A1 adenosine receptors.

We describe here the synthesis and biological activity of new 8-azaadenines bearing both a phenyl group on C(2) and a 9-benzyl group substituted in the ortho position with a Cl or a F atom or a CF(3) group, to verify the synergistic effect of a combination of these substitution patterns on binding with the A(1) adenosine receptors. In position N(6) aliphatic and cycloaliphatic substituents were chosen which had been shown to bind well with the A(1) receptors. Because of the high lipophilicity of these kinds of molecules, we also introduced a hydroxyalkyl substituent in the same position. The compounds obtained generally showed a very good affinity and selectivity for A(1) receptors. Some of the compounds showed K(i) in the nanomolar range, one even in the subnanomolar range (0.6 M). Molecular docking calculations were performed in order to evaluate the interaction energies between the bovine A(1) receptor model and the selected ligands, and then to correlate these energies with biological activities of the ligands as obtained from the experiments. Molecular docking analysis suggests different binding modes towards A(1) receptors that are plausible for these ligands.

Structural modifications of benzanilide derivatives, effective potassium channel openers. X.

Large-conductance calcium-activated potassium (BK) channels are involved in many fundamental cell functions. Consistently, the ability to activate BK channels by exogenous compounds is considered as a promising pharmacodynamic pattern for the potential treatment of several pathologies. In this perspective, the development of new and selective BK-openers can be considered as an actual field of research. This paper reports the synthesis and pharmacological evaluation of new benzanilides, useful for deepening the comprehension of the structure-activity relationships, emerged in previous studies on this class of BK-activators. From a structural point of view, these benzanilides belong to a general class of BK-activators, showing a common pharmacophoric model, consisting of two aryl groups linked through an appropriate "spacer" and the almost obligatory presence of a phenolic hydroxyl. In particular, a new series of benzanilides, in which the phenyl rings have been widely changed both on the acidic portion and the basic one of the amide spacer, were synthesised. Their vasorelaxing effects, induced through the activation of BK channels, were also evaluated. Although many compounds exhibited effects which could not be attributed to the activation of BK channels, two derivatives showed a clear profile of BK-activators with vasodilator activity comparable to or slightly lower than that recorded for the reference benzimidazolone NS1619. A further molecular modelling approach allowed us to obtain a molecular electrostatic potential feature which suggests a suitable interaction with the receptor site of the BK channel, from a tri-dimensional point of view. This approach seems to represent a further contribution for the development of new BK-activators, designed on the basis of the pharmacophoric model above-mentioned.

Heterocyclic analogs of benzanilide derivatives as potassium channel activators. IX.

On the basis of our previous works, addressed to synthesise new activators of BK potassium channels, and of many suggestions from the international literature, a simple pharmacophoric model, consisting of two suitably substituted phenyl rings bound to various kinds of linkers, was hypothesised. In particular, the effectiveness of the amidic linker was demonstrated, since several benzanilide derivatives showed interesting BK-opener properties. As a development of these benzanilides, in this work we introduced heterocyclic substituents, replacing the aryl ring on the acid side or on the basic one of the amide linker of the above pharmacophore. The pharmacological results indicated some relevant remarks about the structural requirements, needed for a satisfactory BK-opener activity. In particular, the presence of a phenolic function, with a possible H-bond donor role, has been confirmed. Furthermore, the presence of nitrogen heterocycles on the acid side of the amide linker seems to be a negative requirement, while furan and thiophene were well tolerated. On the contrary, the introduction of insaturated heterocyclic rings (pyridine and thiazole) on the basic side of the amide linker, led to satisfactory biological activity, while the presence of aliphatic heterocycles lowered the pharmacological effect.