ABSTRACT
In the emerging scenario of patient-centered medicine, it is becoming increasingly important to involve patients in the management of chronic diseases. The rehabilitation field currently has no assessment tool for evaluating the functional impact of post-stroke spasticity on activities of daily living. The aim of this study was to identify a tool to fill this gap. The "Spasticity Questionnaire in Real Life" (SPQR) was administered, twice, to 39 patients with poststroke spasticity. Statistical analysis showed internal consistency and reliability of the questionnaire, with values greater than 0.96 and 0.76, respectively. These results show that the SPQR is a promising tool for evaluating the functional impact of post-stroke spasticity.
Subject(s)
Activities of Daily Living , Muscle Spasticity/diagnosis , Patient Reported Outcome Measures , Severity of Illness Index , Stroke/complications , Surveys and Questionnaires/standards , Aged , Female , Humans , Male , Middle Aged , Muscle Spasticity/etiology , Patient-Centered Care , Reproducibility of Results , Stroke RehabilitationABSTRACT
A series of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives (5a--e and 6a--e) were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D(1) and D(2) dopamine receptors. All compounds showed lower D(1) and D(2) affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline 5a and the 5,6-dihydroxy analogue 6a showed D(2) agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D(1) and D(2) selective ligands.
Subject(s)
Cycloheptanes/chemistry , Cycloheptanes/pharmacology , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacology , Isoquinolines/chemistry , Isoquinolines/pharmacology , Receptors, Dopamine/metabolism , Animals , Cells, Cultured , Cycloheptanes/metabolism , Dopamine Agonists/metabolism , Drug Evaluation, Preclinical , Isoquinolines/metabolism , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Monte Carlo Method , Pituitary Gland, Anterior/cytology , Pituitary Gland, Anterior/drug effects , Pituitary Gland, Anterior/metabolism , Prolactin/drug effects , Prolactin/metabolism , Rats , Receptors, Dopamine/drug effects , Structure-Activity RelationshipABSTRACT
A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones (PQ, 106 compounds), carrying appropriate substituents at the quinoline and N2-phenyl rings, were designed, prepared and tested as central benzodiazepine receptor ligands. Compounds with an affinity significantly higher than the parent compound CGS-8216 were obtained, the most active ligand showing a pIC50 = 10.35. Hansch and comparative molecular field analyses gave coherent results suggesting the main structural requirements of high receptor binding affinity. The possible formation of a three-centred hydrogen bond (HB) at the HB donor site H2, as a key interaction for high receptor binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands.
Subject(s)
Quantitative Structure-Activity Relationship , Receptors, GABA-A/metabolism , Animals , Binding, Competitive , Cerebral Cortex/metabolism , GABA Agonists/chemical synthesis , GABA Agonists/chemistry , GABA Agonists/metabolism , GABA Antagonists/chemical synthesis , GABA Antagonists/chemistry , GABA Antagonists/metabolism , Inhibitory Concentration 50 , Ligands , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Protein Binding , Pyrazoles/metabolism , Quinolones/chemical synthesis , Quinolones/chemistry , Quinolones/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/chemistry , Static ElectricityABSTRACT
Different classes of Peripheral-type Benzodiazepine Receptor (PBR) ligands were examined and common structural elements were detected and used to develop a rational binding model based on energetically allowed ligand conformations. Two lipophilic regions and one electrostatic interaction site are essential features for high affinity ligand binding, while a further lipophilic region plays an important modulator role. A comparative molecular field analysis, performed over 130 PBR ligands by means of the GRID/GOLPE methodology, led to a PLS model with both high fitting and predictive values (r2 = 0.898, Q2 = 0.761). The outcome from the 3D QSAR model and the GRID interaction fields computed on the putative endogenous PBR ligands DBI (Diazepam Binding Inhibitor) and TTN (Tetracontatetraneuropeptide) was used to identify the amino acids most probably involved in PBR binding. Three amino acids, bearing lipophilic side chains, were detected in DBI (Phe49, Leu47 and Met46) and in TTN (Phe33, Leu31 and Met30) as likely residues underlying receptor binding. Moreover, a qualitative comparison of the molecular electrostatic potentials of DBI, TTN and selected synthetic ligands indicated also similar electronic properties. Convergent results from the modeling studies of synthetic and endogenous ligands suggest a common binding mode to PBRs. This may help the rational design of new high affinity PBR ligands.
Subject(s)
Models, Molecular , Peptides/metabolism , Receptors, GABA-A/metabolism , Amino Acid Sequence , Animals , Humans , Ligands , Molecular Sequence Data , Peptides/chemistry , Quantitative Structure-Activity Relationship , Sequence Homology, Amino AcidABSTRACT
2-(1-Piperazinyl)-4H-pyrido[1,2-a]pyrimidin-4-one (5a) is a recently described in vitro inhibitor of human platelet aggregation which specifically inhibits the activity of high affinity cAMP phosphodiesterase. A number of substitution derivatives, isosteres, and analogues of 5a were now synthesized and tested in vitro for their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen, or the Ca2+ ionophore A23187. Among the most effective compounds, the 6-methyl, 8-methyl and 6,8-dimethyl derivatives of 5a resulted nearly as active as the lead when platelet aggregation was induced by ADP or A23187, but less active when collagen was the inducer. On the basis of present results and those previously obtained by us in this and 2-aminochromone structural fields, we have developed a statistically significant 3-D QSAR model, using comparative molecular field analysis (CoMFA), describing the variation of the antiplatelet activity in terms of molecular steric and electrostatic potential changes.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Models, Molecular , Platelet Aggregation Inhibitors/chemistry , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
Diverse series of piperazines linked at N1 to 4, 5, or 6 positions of 3-(2H)-pyridazinone ring and at N4, by a suitable alkyl spacer, to some classical alpha1-adrenoceptor pharmacophore moieties, were tested in vitro for their alpha1-adrenoceptor antagonist activity. The modeling of their biological activity (pKb) by comparative molecular field analysis led to the development of a statistically significant partial least squares (PLS) model able to detect at 3-D level the main physicochemical interactions responsible for alpha1-adrenoceptor antagonist activity.
Subject(s)
Adrenergic alpha-Antagonists/chemistry , Pyridazines/chemistry , Receptors, Adrenergic, alpha-1 , Adrenergic alpha-1 Receptor Antagonists , Adrenergic alpha-Antagonists/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Models, Molecular , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Receptors, Adrenergic, alpha-1/metabolism , Structure-Activity RelationshipABSTRACT
A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin- 3-(3H)-ones, carrying appropriate substituents at the quinoline and N2-phenyl rings, were prepared and tested as central benzodiazepine receptor ligands. Results from structure-affinity relationship studies were in full agreement with previously proposed pharmacophore models and, in addition, quantitative structure-activity analysis gave further significant insight into the main molecular determinants of high benzodiazepine receptor affinity. The intrinsic activity of some active ligands was also determined and preliminary discussed.
