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Raman spectroscopy is widely applied in the cultural heritage field to perform non-destructive measurements in situ, in order to identify materials, specifically pigments. The spectra collected can be challenging to interpret because certain source laser wavelengths may be absorbed by specific pigments, leading to large fluorescence backgrounds which obscure the weak Raman signals, or worse cause photodegradation of the sample. Furthermore, the reference spectra for a specific pigment obtained from a particular laser wavelength is not always available and is a crucial step in the detective work of pigment identification, especially when the resonance Raman effect can enhance some signals. As the range of lasers available increases, spectral libraries do not always record spectra acquired with the same wavelength used to carry out the measurements in field. In this work, reference spectra of 32 different compounds, mostly used in mediaeval manuscripts as pigments and inks, are recorded. Five different wavelengths were used as excitation sources. The aim is to provide a useful and more complete reference source to enable better planning of which laser wavelength is the most appropriate to study a specific set of pigments, and to allow comparisons between spectra acquired with the same wavelength, leading to the unequivocal pigment identification in a step by step manner.

Choline is a quaternary ammonium salt, and being an essential component of different membrane phospholipids (PLs) contributes to the structural integrity of cell membranes. Choline-containing phospholipids (CCPLs) include phosphatidylcholine (PC), sphingomyelin (SM), and choline alphoscerate (GPC). PC is the major phospholipid in most eukaryotic cells. It is involved in SM synthesis, choline/choline metabolite re-generation, and fatty acid/GPC formation. This paper has reviewed chemical, biological and therapeutic features of CCPLs by analyzing: a) effects of exogenous CCPLs, b) influence of GPC treatment on brain cholinergic neurotransmission, and c) neuroprotective effects of GPC alone or in association with acetylcholinesterase inhibitors in animal models of brain vascular injury, d) synthesis of the choline analogs, containing a short alkyl chain instead of a methyl group. Cytidine-diphosphocholine and GPC, protect cell membranes and could be helpful in the sequelae of cerebrovascular accident treatment. Moreover, cellular membrane breakdown is suggested as a feature of neurodegeneration both in acute (stroke) and in chronic (Alzheimer and vascular dementia) brain disorders. Published data were focused to a larger extent on the biosynthesis, relevant role in cell life, and crucial involvement of CCPLs in cholinergic neurotransmission. The possibility of their use in the treatment of cerebrovascular and neurodegenerative disorders is suggested by published clinical studies. In line with these potential practical applications in pharmacotherapy, the need of further research in the field of the synthesis of new choline derivatives with possible activity in nervous system diseases characterized by cholinergic impairment is discussed.

The International Trichinella Reference Centre (ITRC) is the official laboratory of the International Commission on Trichinellosis, of the World Organization for Animal Health and of the European Union Reference Laboratory for Parasites. The ITRC was established in 1988 as a repository of Trichinellastrains and a source of reference materials and information for international scientific research. To date, more than 8000 Trichinellaisolates collected throughout the world have been identified at the species or genotype level by the ITRC staff and the information has been stored in a freely accessible database providing the largest collection of data available for scientists involved in the systematics and epidemiology of this parasite. This paper presents a summary of the data collected over 33 years of activity and describes the database functionalities. It finally advocates the potential of the database to improve knowledge of the epidemiology and taxonomy of Trichinella, which in turn may help the international surveillance of Trichinellaspecies.

Magnetic resonance imaging (MRI) is mandatory to identify the epileptogenic zone in refractory temporal lobe epilepsy (TLE). The correct identification of lesions is essential to obtain good post-surgery seizure control. Low grade tumours (LGT) and focal cortical dysplasia (FCD) are common findings in symptomatic TLE, and frequently coexist. The aim of this study was to identify the MRI characteristics in the diagnosis of FCD associated with LGT. We analyzed 24 subjects with TLE who underwent tailored surgery. They all had LGTs. Two expert neuroradiologists analyzed the imaging data and compared them with histological results, hypothesizing the causes of diagnostic errors in the identification of FCD. We selected three exemplary cases to report the most important causes of errors. In the diagnosis of FCD we reported false positives and false negatives due to different causes. An incomplete MRI protocol, the large dimensions of the tumour, infiltration and related oedema were the most important factors limiting MRI accuracy. MRI can be limited by an incomplete protocol. In addition, the presence of an LGT may limit the neuroradiological diagnosis of FCD in the temporal lobe. Advanced MRI techniques could help reveal subtle lesions that eluded a previous imaging inspection.

The first demonstrations in the early seventies that adenosine had marked effects in the cerebral cortex, which were independent of its role in intermediary metabolism and could be antagonised by methylxanthines, were followed by the observations that other purine derivatives, notably ATP, may also play a critical role in cell function. In 1978 Burnstock first introduced the terms Pl for the nucleoside receptors and P2 for the nucleotide receptors, based on the most fundamental divisions of purine receptors between those for nucleosides such as adenosine and those for nucleotides such as ATP. At present, the P1 (adenosine) receptor family presents 4 subtypes, while the P2 (ATP, ADP and UTP) receptor family has been divided into P2X ionotropic receptors and P2Y metabotropic G proteincoupled receptors (GPCRs). While knowledge on the purinergic receptor pharmacology was increasing, the development of potent and selective ligands for these receptors has been a target of medicinal chemistry research for several decades. In particular, synthesis of 2- substituted adenosines was carried out in many laboratories starting from seventies aimed at finding adenosine derivatives more resistant than the parent nucleoside to rapid uptake into cells, to deamination by adenosine deaminase, and to phosphorylation by adenosine kinase. In the present review the synthesis of alkynyl derivatives of adenine, adenosine, N-alkylcarboxamidoadenosine, and adenine nucleotides, which have been tested on purinergic receptors, will be summarized. Furthermore, the contribution of chemistry, molecular modelling, and pharmacology to the development of structure-activity relationships in this class of purinergic receptor ligands will be outlined.

For a long time, there have been no experimentally determined structural data for any adenosine receptor (AR) and the only approach available for making structure/function correlations about these proteins has been homology modeling. While the early attempts to model these receptors followed the crystallization of bacteriorhodopsin, the cryomicroscopy studies of bovine and frog rhodopsin, and the modeling of a C-template for the TM helices in the rhodopsin family of GPCRs, the crystallization of bovine rhodopsin by Palczewski was of extreme importance as it first provided the crystal structure of an eukaryotic GPCR to be used as template for more realistic homology models. Since then, rhodopsin-based modeling became the routine approach to develop AR structural models that proved to be useful for interpretation of site-directed mutagenesis data and for molecular docking studies. The recently reported crystal structures of the adrenergic beta1 and beta2 receptors only partially confirmed the structural features showed by bovine rhodopsin, raising a question about which template would have been better for further modeling of ARs. Such question remained actually not-answered, due to the publication in late 2008 of the crystal structure of human adenosine A2A receptor (AA2AR). Since its publication, this structure has been used for ligands docking analysis and has provided a high similarity template for homology modeling of the other AR subtypes. Still, the AA2AR crystal structure allows to verify the hypotheses that were made on the basis of the previously reported homology modeling and molecular docking.

Since the discovery of the biological effects of adenosine, the development of potent and selective agonists and antagonists of adenosine receptors has been the subject of medicinal chemistry research for several decades, even if their clinical evaluation has been discontinued. Main problems include side effects due to the ubiquity of the receptors and the possibility of side effects, or to low brain penetration (in particular for the targeting of CNS diseases), short half-life of compounds, lack of effects. Furthermore, species differences in the affinity of ligands make difficult preclinical testing in animal models. Nevertheless, adenosine receptors continue to represent promising drug targets. A2A receptor has proved to be a promising pharmacological target for small synthetic ligands, and while A2A agonists are undergoing clinical trials for myocardial perfusion imaging and as anti-inflammatory agents, A2A antagonists represent an attractive field of research to discover new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Furthermore, the information coming from bioinformatics and molecular modeling studies for the A2A receptor has made easier the understanding of ligand-target interaction and the rational design of agonists and antagonists for this subtype. The aim of this review is to show an overview of the most significant steps and progresses in developing A2A adenosine receptor agonists and antagonists.

Viral infections have menaced human beings since time immemorial, and even today new viral strains that cause lethal diseases are being discovered with alarming frequency. One major example is HIV, the etiological agent of AIDS, which spread up in the last two decades. Very recently, other virus based diseases such as avian flu have spread fear around the world, and hemorrhagic fevers from central Africa serious threaten human health because of their very deadly effects. New antiviral agents are still greatly needed to counter these menaces. Many scientists are involved in this field of research, and many of the recently discovered effective antiviral compounds are nucleoside analogues. Among those derivatives, deazapurine nucleoside analogues have demonstrated potent inhibitory effect of viral replication. This review reports on recently generated data from preparing and testing deazapurine nucleoside derivatives as inhibitors in virus replication systems. Although most of the reported data have been produced in antiHIV, antiHCMV, and antiHSV biological testing, very recently other new important fields of application have been discovered, all in topical subjects of strong interest. In fact, deazapurine nucleosides have been found to be active as chemotherapeutics for some veterinary systemic viral infections, for which no antiviral drugs are licensed yet. Furthermore, they demonstrated efficacy in the inhibition of Hepatitis C virus replication. Finally, these compounds showed high potency as virucides against Ebola Virus, curing Ebola infected mice with a single dose administration.

Glubran2 is a cyanoacrylate-based synthetic glue modified by addition of a second monomer. Among its many advantages over traditional cyanoacrylate products, Glubran2 has a much lower thermal polymerization temperature than that of cyanoacrylates used for cutaneous application. For many years, the new glue has been widely used in neuroradiology endovascular treatments. Our study aimed to assess the use of Glubran2 to treat possible complications arising during the embolization of aneurysms or vascular malformations like AVM or fistulae. A complication encountered in some of these cases is rupture of the vessel wall by the microguide or perforation of the aneurysmal sac by the coils used for embolization. This complication could be overcome by injecting Glubran2 into the rupture point but this would put the glue directly in contact with the subarachnoid space and possibly reach adjacent brain tissue. The aim of this experimental study was to place the glue in direct contact with brain tissue to ascertain its immediate compatibility and tolerability in vivo and any ensuing tissue damage. Three swine underwent neurosurgical procedures and survived for different times after which they were slaughtered and their brains explanted and sent for macroscopic and microscopic investigation by the Pathological Anatomy Service. As a whole, Glubran2 was well tolerated in vivo and did not cause major damage in direct contact with brain tissue.

To combine in the same molecule α1-adrenoreceptor blocking and antioxidant properties, compounds 2−5 were designed and synthesized. All compounds were effective α1-adrenoreceptor antagonists and were tested in both functional and binding assays. In addition, compounds 2 and 5 also displayed significant capacity to inhibit intracellular oxidative stress, whereas 3−5 exerted potent antiproliferative activity in lymph node carcinoma of prostate cells.

The synthesis and preliminary pharmacological profile of a new series of muscarinic antagonists are reported. Discrepancies between binding and functional studies have been found as the compounds of the series do not discriminate among muscarinic subtypes but do show functional selectivity in tissue assays. The most interesting compound 7 shows a good potency and selectivity for the muscarinic M3 receptors present in guinea pig ileum and may be a new lead for further studies.

The discovery of Trichinella zimbabwensis in farm crocodiles of Zimbabwe has opened up a new frontier in the epidemiology of the Trichinella genus. The objective of the present study was to investigate the infectivity of encapsulated species (T. spiralis, T. nativa, T. britovi, T. murrelli and T. nelsoni) and non-encapsulated species (T. pseudospiralis, T. papuae and T. zimbabwensis) in caimans (Caiman crocodilus), varans (Varanus exanthematicus), pythons (Python molurus bivittatus) and turtles (Pelomedusa subrufa) raised at their natural temperature range (26–32 °C). Mice and chickens were used as controls. At 6 days post-infection (p.i.), adult worms were detected in the small intestine of reptiles infected with T. papuae and T. zimbabwensis, of chickens infected with T. pseudospiralis and of mice infected with all encapsulated and non-encapsulated species. At 60 days p.i., T. papuae and T. zimbabwensis adult worms were collected from the intestine of varans and caimans and larvae from muscles of the four reptile species, T. pseudospiralis larvae from muscles of chickens, and larvae of all Trichinella species from mouse muscles. The highest reproductive capacity index of both T. papuae and T. zimbabwensis was observed in varans. The results show that T. papuae and T. zimbabwensis are able to complete their entire life-cycle in both poikilothermic and homoiothermic animals.

In a search for structurally new α1-adrenoreceptor (α1-AR) antagonists, prazosin (1)-related compounds 2−11 were synthesized and their affinity profiles were assessed by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D) and by binding assays in CHO cells expressing human cloned α1-AR subtypes. Transformation of the piperazinylquinazoline moiety of 1 into an aminomethyltetrahydroacridine system afforded compound 2, endowed with reduced affinity, in particular for the α1A-AR subtype. Then, to investigate the optimal features of the tricyclic moiety, the aliphatic ring of 2 was modified by synthesizing the lower and higher homologues 3 and 4. An analysis of the pharmacological profile, together with a molecular modeling study, indicated the tetrahydroacridine moiety as the most promising skeleton for α1-antagonism. Compounds 5−8, where the replacement of the furoyl group of 2 with a benzoyl moiety afforded the possibility to evaluate the effect of the substituent trifluoromethyl on receptor binding, resulted, except for 7, in a rather surprising selectivity toward α1B-AR, in particular vs the α1A subtype. Also the insertion of the 2,6-dimethoxyphenoxyethyl function of WB 4101 on the tetrahydroacridine skeleton of 2, and/or the replacement of the aromatic amino function with a hydroxy group, affording derivatives 9−11, resulted in α1B-AR selectivity also vs the α1D subtype. On the basis of these results, the tetrahydroacridine moiety emerged as a promising tool for the characterization of the α1-AR, owing to the receptor subtype selectivity achieved by an appropriate modification of the lateral substituents.

1,3-Dioxolane-based compounds (2−14) were synthesized, and the pharmacological profiles at α1-adrenoceptor subtypes were assessed by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Compound 9, with a pA2 of 7.53, 7.36, and 8.65 at α1A, α1B, and α1D, respectively, is the most potent antagonist of the series, while compound 10 with a pA2 of 8.37 at α1D subtype and selectivity ratios of 162 (α1D/α1A) and 324 (α1D/α1B) is the most selective. Binding assays in CHO cell membranes expressing human cloned α1-adrenoceptor subtypes confirm the pharmacological profiles derived from functional experiments, although the selectivity values are somewhat lower. Therefore, it is concluded that 1,3-dioxolane-based ligands are a new class of α1-adrenoceptor antagonists.

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 M2 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 pKa) and the AChE inhibitory potency (pIC50) of tertiary amine compounds 6−12, which was confirmed by the invariance of the pIC50 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 pIC50 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 (pAI50 for reversing the neuromuscular blockade was 6.45 (±0.07)), as well as the ability to antagonize the M2 receptors (pKb = 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.

The present article expands on the study of another aspect of structure−activity relationships of the polymethylene tetraamines, namely, the effect of inserting the tetraamine backbone into a macrocyclic structure. To this end, compounds 8−12 were designed by linking the two terminal nitrogen atoms of prototype methoctramine 2 to an aryl moiety. Alternatively, 2 was first modified to achieve compounds 6 and 7, which in turn were cyclized by linking the two terminal primary amine functions to a polyphenyl spacer, affording 13−20. All the compounds were tested on muscle-type nAChRs and most of them as well on AChE. Furthermore, selected compounds were tested also on peripheral M2 and M3 mAChRs. All these cyclic derivatives, like prototypes, were potent noncompetitive antagonists at both frog and Torpedo nAChRs, suggesting that polyamines do not need to be linear or in extended conformation to optimally interact with the nicotinic channel; rather, they may bind in a U-shaped conformation. Relative to muscarinic activity, macrocyclic compounds 10, 13, 14, and 20, in contrast with the profile displayed by 2, were almost devoid of affinity. It is derived that an aryl spacer is detrimental to the interaction of polyamines with mAChRs. Finally, all the diamine diamides investigated in this study were much less potent in inhibiting AChE activity than prototype 3, suggesting that a macrocyclic structure may not be suitable for AChE inhibition.

Polymethylene tetraamine methoctramine (1) is a prototypical antimuscarinic ligand endowed with a significant affinity for muscular nAChRs. Thus, according to the universal template approach, structural modifications were performed on 1 in order to improve affinity and selectivity for the muscle-type nAChR. The polyamine derivatives synthesized were tested at both frog rectus and Torpedo nAChRs and at guinea pig left atria (M2) and ileum longitudinal muscle (M3) mAChRs. All of the compounds, like prototype 1, were noncompetitive antagonists of nicotinic receptors while being competitive antagonists at M2 and M3 mAChRs. The biological profile of polyamines 4−7 revealed that increasing the number of amine functions and the chain length separating these nitrogen atoms led to a significant improvement in potency at nAChRs. Moreover, the role of the number and type of amine functions in the interaction with nAChRs was further investigated through the synthesis of compounds 9 and 10. Tetraamines 8 and 11, bearing a rather rigid spacer between the nitrogen atoms instead of the very flexible polymethylene chain, displayed a profile similar to that of 1 at nAChRs, whereas a significant decrease in potency was observed at mAChRs. Tetraamine 12, bearing a 2-methoxyphenethyl group, was less potent than 1, whereas tetraamine 13, carrying a diphenylethyl moiety, was more potent than 1, confirming that an increase in size of the hydrophobic group on the terminal nitrogen atoms increases significantly the binding affinity for nAChRs. Tetraamines 14−17 were significantly more potent than prototype 2 at both frog rectus and Torpedo nAChRs, confirming that an increase in the distance between the amine functions results in a parallel increase in the affinity for nAChRs. To gain insight into the mode of interaction of polymethylene tetraamines with nAChRs, photolabile (19 and 20) and fluorescent (21 and 22) compounds were synthesized. A most intriguing finding was the observation that 19, which bears two identical azido groups on the terminal nitrogen atoms, was found to bind the Torpedo nAChR with a 1:1 stoichiometry, suggesting a U-shaped conformation in the receptor interaction. Moreover, the high potency shown by fluorescent compounds 21 and 22 appears promising for a further characterization of the polymethylene tetraamines binding site with the muscle-type nAChR.

WB4101 (1)-related compounds 5−10 were synthesized, and their biological profile at α1-adrenoreceptor (AR) subtypes and 5-HT1A serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors. Moreover, their receptor selectivity was further determined in functional experiments in isolated rat prostate (α1A), vas deferens (α1A), aorta (α1D), and spleen (α1B). In functional assays, compound 5 was the most potent at α1D-ARs with a reversed selectivity profile (α1D > α1A > α1B) relative to both prototype 1 and phendioxan (2) (α1A > α1D > α1B), whereas compound 8, bearing a carbonyl moiety at position 1, was the most potent at α1A-ARs with a selectivity profile similar to that of prototypes. The least potent of the series was the trans isomer 6, suggesting that optimum α1-AR blocking activity in this series is associated with a cis relationship between the 2-side chain and the 4-phenyl ring rather than a trans relationship as previously observed for the 2-side chain and the 3-phenyl ring in 2 and related compounds. Binding affinity results were not in complete agreement with the selectivity profiles deriving from functional experiments. Although a firm explanation was not available, neutral and negative antagonism and receptor dimerization were considered as two possibilities to account for the difference between binding and functional affinities. Finally, compound 5 was selected for a modeling study in comparison with 1, mephendioxan (3), and open phendioxan (4) to achieve information on the physicochemical interactions that account for its high affinity toward α1d/D-ARs.

A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating α2-adrenoreceptors selectivity versus both α1-adrenoreceptors and I2 imidazoline binding sites. The most potent α2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the α2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15).³⁰ (S)-(−)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with α2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with α2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective α2-antagonist RX821002.

Hybrid tetraaamine disulfides 4−9 were synthesized by combining the structural features of prazosin (1), a competitive α1-adrenoreceptor antagonist, and benextramine (2), an irreversible α1/α2-adrenoreceptor antagonist, and their biological profiles at α1-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). To verify the role of the disulfide moiety on the interaction with α1-adrenoreceptor subtypes, carbon analogues 10−15 were included in this study. All quinazolines lacking the disulfide bridge behaved, like 1, as competitive antagonists, whereas all polyamine disulfides displayed a nonhomogeneous mechanism of inhibition at the three subtypes since they were, like 2, noncompetitive antagonists at the α1A and α1B subtypes while being, unlike 2, competitive antagonists at the α1D. In particular, the blocking effects were characterized by a decrease of the maximal response to noradrenaline that was affected only slightly by washings. Probably the α1A and α1B subtypes bear in the binding pocket a suitable thiol function that would suffer an interchange reaction with the disulfide moiety of the antagonist and which is missing, or not accessible, in the α1D subtype. Polyamines 8, 9, and 14, among others, emerged as promising tools for the characterization of α1-adrenoreceptors, owing to their receptor subtype selectivity. Finally, the effect of nonbasic substituents on the phenyl ring of prazosin analogues 16−28 on potency and selectivity for the different subtypes can hardly be rationalized.

WB 4101-related benzodioxans 3−9 were synthesized, and their biological profiles at α1-adrenoreceptor subtypes and 5-HT1A serotoninergic receptors were assessed by binding assays in CHO and HeLa cells membranes expressing the human cloned receptors. Furthermore, receptor selectivity of selected benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens (α1A) and aorta (α1D) and guinea pig spleen (α1B), in additional receptor binding assays in rat cortex membranes containing α2-adrenoreceptors and 5-HT2 serotoninergic receptors, and in rat striatum membranes containing D2 dopaminergic receptors. An analysis of the results of receptor binding experiments for benzodioxan-modified derivatives 3−9 showed high affinity and selectivity toward the α1a-adrenoreceptor subtype for compounds 3−5 and 7 and a reversed selectivity profile for 9, which was a selective α1d antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4101) led to a marked decrease in the affinity for 5-HT1A serotoninergic receptors, which may have relevance in the design of selective α1A-adrenoreceptor antagonists. The exception to these findings was the chromene derivative 8, which exhibited a 5-HT1A partial agonist profile.

The four homochiral 4-deoxy-4,4-difluoromuscarine stereoisomers (difluoromuscarines) were prepared in very high enantiomeric excess. A convenient sequence based on the use of natural as well as “unnatural” ethyl lactate allowed the synthesis of target compounds, whose absolute configuration is dictated by that of the starting synthon. Quaternary ammonium salts (+)-5, (−)-5, (−)-6, and (+)-6 were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M2 (heart) and M3 (ileum and bladder) muscarinic receptor subtypes. The eutomer (+)-5 and distomer (−)-5 were also tested in vivo on pithed rat, and their muscarinic activity at the M1 receptor subtype was compared with those of racemic muscarine [(±)-1] and (2S,4R,5S)-4-deoxy-4-fluoromuscarine [(+)-4]. Further pharmacological parameters such as affinity, relative efficacy, and enantioselectivity have been determined for compounds (+)-5 and (−)-5 at M2 (heart force and rate) and M3 (ileum and bladder) receptors in order to investigate muscarinic receptor heterogeneity. The four homochiral difluoromuscarines behave as muscarinic agonists in all the tests with a potency trend which is different from that previously observed with the 4-deoxy-4-fluoromuscarines and (±)-1, thus indicating the intervention of the second fluorine atom on the receptor−ligand interaction. Moreover, the second fluorine atom produces significant differences in the affinity and relative efficacy values of compounds (+)-5 and (−)-5 at M2 and M3 subtypes, which could be attributed to a heterogeneity between the muscarinic receptors mediating heart rate and heart force and those involved in the contraction of ileum and bladder.

Summary: The agonistic potencies of ()muscarine, ()cis - 2 - methyl - 5 - [(dimethylamino)methyl] - 1,3 -oxathiolane methiodide (cis-oxathiolane) and its two enantiomers were determined at muscarinic M1 and M2 receptors in the pithed rat. In non-pretreated animals, i.v. administration of these agents produced bradycardic effects mediated by cardiac M2 receptors followed by increases in heart rate mediated by M1 receptors in sympathetic ganglia. As these responses have been shown to partly overlap, “true” M1 and M2 potencies were determined after selective blockade of M1 and M2 receptors by pirenzepine and methoctramine, respectively. A similar rank order of agonist potencies was obtained at M1 and M2 receptors: (+)cis-oxathiolane > ()cis-oxathiolane > ()muscarine > (-)cis-oxathiolane. At both receptor subtypes, (+)cis-oxathiolane was considerably more potent (ca. 30-fold) than its corresponding (−) enantiomer indicating that the agonist binding sites of the two receptor subtypes may have similar stereochemical properties. While ()muscarine showed similar potencies at M1 and M2 receptors, racemic cis-oxathiolane and its two enantiomers showed a slight selectivity (3–7 fold) for M1 receptors indicating the potential usefulness of these compounds in the development of selective M1 receptor agonists.

Background As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. Methods Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. Results Two hundred sixty-seven GBM patients (median age, 64 y; range, 29–84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2–12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0–18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248–0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388–0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328–0.986; P = .0446). Conclusions The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.

For Abstract see ChemInform Abstract in Full Text.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.