Biomedical subjects

Maurizio Recanatini

Publications and source records attributed to Maurizio Recanatini.

29 records · Page 2Linked to original sources

PubMed2004

Acetylcholinesterase inhibitors as a starting point towards improved Alzheimer's disease therapeutics.

The knowledge about the pathogenesis and the development of the neurodegeneration associated with Alzheimer's disease (AD) has been organised throughout the years into two theories, namely the cholinergic and the amyloid hypotheses. The loss of cholinergic neurotransmission and the abnormal aggregation and deposition of the amyloid-beta peptide (A beta) in the brain are retained as the central events by the two theories, respectively. These phenomena and their pathological consequences are the main targets of the drug discovery strategies based on each hypothesis. However, the two paradigms share some common aspects as shown by several experimental evidences, such that they might even fit into a unifying scenario of neuropathology and neurodegeneration. In this context, in a perspective of drug discovery, the enzyme acetylcholinesterase (AChE) holds a key position, as it is a main target for cholinomimetic AD drugs being responsible for the breakdown of the neurotransmitter, and it is also involved in the aggregation of A beta and the formation of the neurotoxic fibrils. Following this view, in recent years, a drug design strategy has emerged, directed to finding molecules able to inhibit both of these actions exerted by AChE. In this review, we will briefly introduce the biological basis of this strategy, and then will account for the early results obtained in this field in our and in other laboratories. The main focus will be on potential lead compounds for which some experimental evidence exists supporting the hypothesis of their dual action, as AChE inhibitors and blockers of the AChE-induced A beta aggregation.

Alzheimer Disease↗

PubMed2003

Density functional study of the enzymatic reaction catalyzed by a cyclin-dependent kinase.

Density functional theory (DFT) calculations were carried out to study the molecular mechanism of the phosphoryl transfer reaction catalyzed by cyclin-dependent kinases (CDKs). The DFT study presented here shows that CDKs catalyze the phosphoryl transfer reaction from ATP to the serine substrate through a single step mechanism with a SN2-like transition state.

Catalysis↗

PubMed2003

3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer's disease therapy.

In recent years, the investigation of acetylcholinesterase (AChE) inhibitors has gained further interest, because the involvement of the peripheral site of the enzyme in the beta-amyloid (Abeta) aggregation process has been disclosed. We present here, for the first time, a direct evidence of the Abeta antiaggregating action of an AChE inhibitor (AP2238) purposely designed to bind at both the catalytic and the peripheral sites of the human enzyme.

Acetylcholinesterase↗

PubMed2003

Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and nitrogen atoms of caproctamine.

Continuing our studies on polyamine-based compounds of potential interest in the field of Alzheimer's disease therapeutics, we investigated the structure-activity relationships (SAR) of a lead compound (caproctamine, 3) identified in a previous work. In particular, we varied the substituents on the phenyl ring and on the nitrogen functions (both the amine and the amide), and studied the effects of such modifications on the inhibitory potency against isolated acetyl- and butyryl-cholinesterase (AChE and BChE). Moreover, the ability of selected compounds to reverse the d-tubocurarine-induced neuromuscular blockade and their antagonism toward muscarinic M(2) receptors in guinea pig left atrium were assayed. The most interesting SAR result was the identification of a relationship between the electronic characteristics of 2-substituents (measured by pK(a)) and the AChE inhibitory potency (pIC(50)) of tertiary amine compounds 6-12, which was confirmed by the invariance of the pIC(50) values of the corresponding methiodide derivatives 14-20. With regard to the biological profile, the most interesting compound was the N-ethyl-analogue of caproctamine (9), that showed pIC(50) values of 7.73 (+/-0.02) and 5.65 (+/-0.03) against AChE and BChE, respectively. The ability to increase the acetylcholine level was maintained in the functional assay (pAI(50) for reversing the neuromuscular blockade was 6.45 (+/-0.07)), as well as the ability to antagonize the M(2) receptors (pK(b) = 5.65 (+/-0.06)). Moreover, 9 showed a long duration of action as AChE inhibitor, an useful property in view of a possible development of this compound as a therapeutic agent.

Acetylcholinesterase↗

PubMed2003

Synthesis and antagonistic activity at muscarinic receptor subtypes of some derivatives of diphenidol.

A series of new derivatives, related to diphenidol and to its 2-carbonyl analogue, were designed as antimuscarinic agents. The synthesized compounds were evaluated both as hydrochlorides and as methiodides by functional tests at guinea-pig heart (M(2)), guinea-pig ileum (M(3)) and rabbit vas deferens (putative M(4)). Two derivatives (3a and 5a) showed an M(3)-selective profile similar to that of the reference compounds, though they resulted less potent.

Animals↗

PubMed2002

Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.

In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.

Anti-Arrhythmia Agents↗

PubMed2002

Looking for selectivity among cytochrome P450s inhibitors.

Cytochrome P450s 19 and 17 are very important pharmacological targets in two different fields of cancer chemotherapy. We present here a theoretical study aimed at explaining the molecular basis of inhibitor affinity and selectivity for either P450 19 or P450 17. Docking simulations of two compounds pointed out the major physicochemical features associated with inhibitory activity. Our results, in agreement with site-directed mutagenesis experiments, could be of relevant utility when designing new P450 19 and P450 17 inhibitors.

Amino Acid Sequence↗

PubMed2002

Nonsteroidal aromatase inhibitors: recent advances.

Aromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure-activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase-inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly.

Animals↗

PubMed2002

Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview.

The long and growing list of non-antiarrhythmic drugs associated with prolongation of the QT interval of the electrocardiogram has generated concern not only for regulatory interventions leading to drug withdrawal, but also for the unjustified view that QT prolongation is usually an intrinsic effect of a whole therapeutic class [e.g. histamine H(1) receptor antagonists (antihistamines)], whereas, in many cases, it is displayed only by some compounds within a given class of non-antiarrhythmic drugs because of an effect on cardiac repolarisation. We provide an overview of the different classes of non-antiarrhythmic drugs reported to prolong the QT interval (e.g. antihistamines, antipsychotics, antidepressants and macrolides) and discusses the clinical relevance of the QT prolonging effect. Drug-induced torsade de pointes are sometimes considered idiosyncratic, totally unpredictable adverse drug reactions, whereas a number of risk factors for their occurrence is now recognised. Widespread knowledge of these risk factors and implementation of a comprehensive list of QT prolonging drugs becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia, hypocalcaemia), impaired hepatic/renal function, concomitant treatment with other drugs with known potential for pharmacokinetic/pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class I or III antiarrhythmic agents). This review provides insight into the strategies that should be followed during a drug development program when a drug is suspected to affect the QT interval. The factors limiting the predictive value of preclinical and clinical studies are also outlined. The sensitivity of preclinical tests (i.e. their ability to label as positive those drugs with a real risk of inducing QT pronglation in humans) is sufficiently good, but their specificity (i.e. their ability to label as negative those drugs carrying no risk) is not well established. Verapamil is a notable example of a false positive: it blocks human ether-a-go-go-related (HERG) K(+) channels, but is reported to have little potential to trigger torsade de pointes. Although inhibition of HERG K(+) channels has been proposed as a primary test for screening purposes, it is important to remember that several ion currents are involved in the generation of the cardiac potential and that metabolites must be specifically tested in this in vitro test. At the present state of knowledge, no preclinical model has an absolute predictive value or can be considered as a gold standard. Therefore, the use of several models facilitates decision making and is recommended by most experts in the field.

Anti-Bacterial Agents↗

PubMedDate not supplied

Heterocyclic inhibitors of AChE acylation and peripheral sites.

Notwithstanding the criticism to the so called " cholinergic hypothesis", the therapeutic strategies for the treatment of Alzheimer's disease (AD) have been mainly centered on the restoration of cholinergic functionality and, until the last year, the only drugs licensed for the management of AD were the acetycholinesterase (AChE) inhibitors. Target enzyme AChE consists of a narrow gorge with two separate ligand binding sites: an acylation site at the bottom of the gorge containing the catalytic triad and a peripheral site located at the gorge rim, which encompasses binding sites for allosteric ligands. The aim of this short review is to update the knowledge on heterocyclic AChE inhibitors able to interact with the two sites of enzymes, structurally related to the well known inhibitors physostigmine, rivastigmine and propidium. The therapeutic potential of the dual site inhibithors in inhibiting amyloid-beta aggregatrion and deposition is also briefly summarised.

Acetylcholinesterase↗

PubMedDate not supplied

A comparative study on the application of hierarchical-agglomerative clustering approaches to organize outputs of reiterated docking runs.

Reiterated runs of standard docking protocols usually provide a collection of possible binding modes rather than pinpoint a single solution. Usually, this ensemble is then ranked by means of an energy-based scoring function. However, since many degrees of approximation have to be introduced in the computation of the binding free energy, scoring functions cannot always rank the experimental pose among the top scorers. Cluster analysis might help to overcome this limit, provided that data clusterability has been earlier assessed. In this paper, first, we present a modified version of a test earlier developed by Hopkins to assess whether or not docking outputs show the natural tendency to be grouped in clusters. Then, we report the results of a comparative study on the application of different hierarchical-agglomerative cluster rules to partition docking outputs. The rule that was able to best manage the observed data was finally applied to the whole ensemble of poses collected from several docking tools. The combination of the average linkage rule with the cutting function developed by Sutcliffe and co-workers turned out to be an approach that meets all of the criteria required for a robust clustering protocol. Furthermore, a consensus clustering allowed us to identify the pose closest to the experimental one within a statistically significant cluster, whose number was always of few units.

Adenine↗