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We have recently reported a novel class of selective 5-HT1A agonists among which GF449 emerged for its high potency and almost full agonist activity (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 91.6). In order to quantify GF449 in rat plasma and brain, a sensitive LC-MS/MS method was developed and validated. Solid phase extraction (SPE) or a combined protein precipitation SPE permitted an efficient analyte recovery and sample clean-up. Multiple reaction monitoring (MRM) was used to track both GF449 and its internal standard (IS), MM189. GF449 was determined and quantitated to nanomolar concentrations in both plasma and brain matrix (LOQs = 0.0025 nmol/mL). Specificity was ensured using three further MRM qualifier transitions for both analyte and IS. Linearity was found in the range of 0.0025 nmol/mL to 1.00 nmol/mL (R2 = 0.9965) and from 0.0025 nmol/mL to 50 nmol/mL (R2 = 0.9999) for plasma and brain respectively. Intraday trueness ranged from 94.0% to 117.5% for brain and from 93.7% to 108.1% for plasma, while precision values were within 3.0% - 6.7% and 2.5% - 9.2% for plasma and brain respectively. The interday trueness of plasma ranged from 89.6% to 107.7% and the precision values (CV%) ranged from 4.6% to 7.5%. Interday trueness and precision (CV%) of the brain ranged from 94.3% to 101.2% and from 1.6% to 11.5% respectively. The method was validated in accordance with the EMEA guidelines and was successfully applied to plasma and brain samples obtained from rats treated with a 10 mg/kg single oral dose of GF449, thus demonstrating its applicability to preclinical pharmacokinetic studies.

A series of 1,3-oxathiolane-based nucleoside analogs 5-methyl substituted was synthesized and tested as potential antiviral agents. Structural characterization and C2-C4 / C2-C5 relative stereochemistry assignments were performed by NMR experiments. All tested isomers were found to be inactive and cytotoxic.

A stopped‐flow bidimensional recycle HPLC (sf‐BD‐rHPLC) configuration has been used to investigate simultaneously the stereo and chemical stability of labile chiral compounds. The single enantiomers of a racemate can be separated on chiral column (first dimension) and each one can be trapped in the achiral column (second dimension) that works as reactor.By filling the achiral column with the appropriate aqueous buffers it is possible to evaluate the stability of the trapped enantiomer toward aqueous buffer itself. It was possible to recycle the reaction products formed in the chiral column (first dimension) where they are separated by a second six valve port. The reaction rate constants were calculated for the different processes occurred in the achiral column by means of corresponding peak areas. The method was applied to a pharmacological active compound: (±)7‐chloro‐5‐ethyl‐3‐methyl‐3,4‐dihydro‐2H‐benzo[1,2,4]thiadiazine 1,1‐dioxide ((±)‐1) to evaluate enantiostability and hydrolysis in conditions similar to those of biological fluid. A classical batchwise kinetic method was used to calculate rate constants of hydrolysis and enantiomerization at the same temperature and in the same solvents used in sf‐BD‐rHPLC. The good agreement of the results obtained validate the novel procedure developed. Furthermore, the results generated off‐line were used to determine the influence of solvents on the racemization of (±)‐1. Chirality, 2011. © 2011 Wiley‐Liss, Inc.

In the attempt to define more accurately structure−affinity relationships for σ1 and σ2 ligands, we synthesized and tested on σ subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine, in which the effect of modifications on the aralkyl moiety was studied in a systematic way. The affinity of the compounds here described varied to a great extent, with a σ2/σ1 selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative to bind to σ1 receptors in a different way than piperidines, we synthesized and tested a series of piperazine compounds; the comparison of their affinity with that of the corresponding piperidines strongly supports the possibility of a different binding mode. While the compounds here described are on the whole selective for σ vs serotonin 5-HT1A and dopamine D2 receptors, 9aa, 9ba and 9ab possess a remarkable affinity for both σ and 5-HT1A receptors, with Ki in the nanomolar range, and are selective with respect to D2 receptors. They displayed also a partial agonist profile in a human 5-HT1A [³⁵S]GTPγS binding assay, suggesting their potential use as atypical antipsychotic agents.

The α- and β-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and the corresponding enantiomers were prepared and tested with the purpose of studying the role played by the ethylene bridge in modulating I1- and I2-IBS selectivity. The α-methylation appeared to be extremely critical regarding the affinity and selectivity for the I1-IBS subtypes (I1/I2 = 186 for imidazoline 7) and the stereospecificity of interaction (eudismic ratio (S)-(−)-7/(R)-(+)-7 = 5888). Instead, even if in a more limited fashion, the β-methylation tended toward I2-IBS selectivity (I2/I1 = 50 for imidazoline 8). The unsubstituted compound 4 (I2/I1 = 1479) proved to be considerably more potent and selective with respect to I2-IBS subtypes.

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.

We describe a rare congenital malformation of the spine known as ‘butterfly’ vertebra, which is classified as a congenital developmental anomaly in the early embryonic period, resulting in a sagittally cleft vertebral body. In our case, the anomaly affects an adult female and involves the fifth lumbar vertebra and first sacral vertebra; it is not associated with other anomalies of the spine. Copyright © 2002 John Wiley & Sons, Ltd.

We describe a rare congenital malformation of the spine known as ‘butterfly’ vertebra, which is classified as a congenital developmental anomaly in the early embryonic period, resulting in a sagittally cleft vertebral body. In our case, the anomaly affects an adult female and involves the fifth lumbar vertebra and first sacral vertebra; it is not associated with other anomalies of the spine. Copyright © 2002 John Wiley & Sons, Ltd.

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.

Methylation of the carbon atom C1 of compound 1, a potent and not selective muscarinic antagonist, was carried out. The resulting diastereomers were separated and the corresponding racemate further resolved to give four enantiomers, which were tested both as hydrogen oxalate and methiodide salts. The pharmacological results obtained at M1, M2and M3muscarinic receptor subtypes, show that methylation at C1, depending on the stereochemistry, increases antagonist potency, having thus the same effect of nitrogen quaternization. These results may well lead to the development of new potent antimuscarinic drugs lacking a cationic head.

Clonidine and benazoline are two structurally related imidazolines. Whereas clonidine binds both to α2-adrenoceptors (α2R) and to I1imidazoline receptors (I1R), benazoline showed a high selectivity for imidazoline receptors. Although the α2R are negatively coupled to adenylate cyclase, no effect on cAMP level by activation of I1R has been reported so far. We therefore aimed to compare the effects of clonidine and benazoline on forskolin-stimulated cAMP levels in cell lines expressing either I1R only (PC12 cells), α2R only (HT29 cells), or I1R and α2R together (NG10815 cells). Clonidine proved able to decrease the forskolin-stimulated cAMP level in the cells expressing α2R and this effect could be blocked by rauwolscine. In contrast, in cells lacking these adrenoceptors, clonidine had no effect. On the other hand, benazoline and other I1receptor-selective imidazolines decreased forskolin-stimulated cAMP level in the cells expressing I1R, in a rauwolscine- and pertussis toxin-insensitive manner. These effects were antagonized by clonidine. According to these results, we demonstrated that 1) α2R and I1R are definitely different entities because they are expressed independently in different cell lines; 2) α2R and I1R are both implicated in the cAMP pathway in cells (one is sensitive to pertussis toxin and the other is not); and 3) I1R might be coupled to more then one transduction pathway. These new data will be essential to further understand the physiological implications of the I1R and the functional interactions between I1receptors and α2-adrenoceptors.

Clonidine and benazoline are two structurally related imidazolines. Whereas clonidine binds both to alpha(2)-adrenoceptors (alpha(2)R) and to I(1) imidazoline receptors (I(1)R), benazoline showed a high selectivity for imidazoline receptors. Although the alpha(2)R are negatively coupled to adenylate cyclase, no effect on cAMP level by activation of I(1)R has been reported so far. We therefore aimed to compare the effects of clonidine and benazoline on forskolin-stimulated cAMP levels in cell lines expressing either I(1)R only (PC12 cells), alpha(2)R only (HT29 cells), or I(1)R and alpha(2)R together (NG10815 cells). Clonidine proved able to decrease the forskolin-stimulated cAMP level in the cells expressing alpha(2)R and this effect could be blocked by rauwolscine. In contrast, in cells lacking these adrenoceptors, clonidine had no effect. On the other hand, benazoline and other I(1) receptor-selective imidazolines decreased forskolin-stimulated cAMP level in the cells expressing I(1)R, in a rauwolscine- and pertussis toxin-insensitive manner. These effects were antagonized by clonidine. According to these results, we demonstrated that 1) alpha(2)R and I(1)R are definitely different entities because they are expressed independently in different cell lines; 2) alpha(2)R and I(1)R are both implicated in the cAMP pathway in cells (one is sensitive to pertussis toxin and the other is not); and 3) I(1)R might be coupled to more then one transduction pathway. These new data will be essential to further understand the physiological implications of the I(1)R and the functional interactions between I(1) receptors and alpha(2)-adrenoceptors.

Several analogues of cirazoline (2Chart 1), a selective α1-adrenoreceptor agonist, were prepared and their pharmacological profiles studied. Although at the α1-adrenoreceptor all the compounds displayed a significant agonist activity, at the α2-adrenoreceptor they showed either agonist or antagonist activity depending on the nature of the phenyl substituent. The qualitative structure–activity relationship led us to the conclusion that the oxygen atom in the side-chain is essential for α1-agonist activity, while the cyclopropyl ring is not, and may be replaced by several groups. Of the groups studied, isopropoxy appears to be the best. Instead, the same substitution (i.e., isopropoxy for the cyclopropyl ring) at α2-adrenoreceptors causes a reversal of activity. On the other hand, the cyclopropyl ring seems to be important for α1-selectivity. Compound 20is the most potent α1-agonist of the series, being equiactive with cirazoline on rat vas deferens and in pithed rat.

Analysis of digital and palmar dermatoglyphics in an Italian mountain population was carried out. Dermatoglyphic variability was particularly investigated in samples from four different valleys. Microgeographical differences in qualitative and quantitative traits among valleys were found. The relationship between degree of endogamy and dermatoglyphic differences is discussed. The biological repercussion of isolation in the history of this Apennine population is also pointed out by means of comparisons with a nearby plains population characterized by low inbreeding.

A series of 2- trans -styryl-imidazoline ( tracizoline ) congeners were designed and tested to develop 2-D and 3-D QSAR models for their binding to imidazoline (I 2 ) receptor. The important role of lipophilicity was assessed by classical 2-D QSAR study (Hansch approach) and by comparative molecular field analysis (CoMFA) with the inclusion of the molecular lipophilicity potential (MLP), as an additional descriptor, besides standard steric and electrostatic fields. Results from these studies were compared to those obtained in a previous modeling study of I 2 receptor ligands and integrated into a new, comprehensive model, based on about sixty I 2 receptor ligands. This model revealed, at the three-dimensional level, the most significant steric, electrostatic, and lipophilic interactions accounting for high I 2 receptor affinity.

An der eisenzeitlichen Bevölkerung von Monte Bibele (Bologna, Italien) wird der Gesundheitszustand untersucht. Am häufigsten ist die Wirbelsäule von krankhaften Veränderungen betroffen: Gespaltener Atlas, Spina bifida des Sacrums, Sacralisation des 5. Lumbarwirbels, Arthrose. Auch im Hüft-, Ellbogen-, Schulter- und Kniebereich konnte Arthrose beobachtet werden. Brüche sind nicht selten. Ebenso konnten Periostitis and Osteoporose sowie ein vermutlicher Fall von Akromegalie beobachtet werden. Die Mehrzahl der in der Bevölkerung von Monte Bibele vorhandenen pathologischen Veränderungen dürften auf Alterungsprozesse oder auf Belastung durch körperliche Arbeit zurückzuführen sein.

In an attempt to further improve the α-adrenoreceptor blocking activity of benextramine, the effect of heteroaromatic substituents on the terminal nitrogens was studied. In this communication we report on the newly synthetized N,N″-(dithio-2,1-ethanediyl)bis{N′-(pyrrol-2-ylmethyl)-1,6-hexanediamine} (pyrextramine) that displayed higher affinity (5–10-fold) and higher selectivity (about 12-fold) than benextramine. These preliminary results show that pyrextramine can replace benextramine in the elucidation and characterization of the peripheral α1-adrenoreceptors.

To elucidate the molecular requirements of the active sites of cholinergic receptors, 3-methyl-4-oxo-1-(N,N-dimethylaminomethyl)cyclopent-2-ene methiodide (2,3-dehydrodeoxamuscarone) and cis- and trans-3-methyl-4-hydroxy-1-(N,N-dimethylaminomethyl)cyclopent-2-ene methiodides (cis- and trans-dehydrodeoxamuscarines) were synthesized and tested. The results, compared with those of the corresponding oxygenated compounds, seem to indicate that 2,3-dehydrodeoxamuscarines and muscarine bind at the same site while 2,3-dehydrodeoxamuscarone interacts with the site normally occupied by muscarone. Furthermore, the previously suggested hypothesis that the unpolar site might somehow incorporate that of muscarone was considered.

Zahnkrankheiten und -abnutzung bieten wertvolle Informationen bezüglich Ernährung und Nahrungszubereitung in früheren menschlichen Bevölkerungen. In dieser Untersuchung werden die Zähne einer eisenzeitlichen Bevölkerung von Monte Bibele (Bologna) analysiert, um ihre Ernährungssituation zu rekonstruieren. Frequenz und Verbreitung von Zahnkaries lassen auf einen beträchtlichen Konsum von Kohlenhydraten schließen, was mit der angenommenen agrarischen Lebensweise dieser Bevölkerung in Einklang steht. Zahnsteinbildungen sprechen für einen gewissen Proteinanteil in der Ernährung. Die Häufigkeit von antemortalen Zahnverlusten sowie von Zahnabszessen stimmen mit den Befunden bezüglich Karies und Steinbildungen überein. Insgesamt zeigte sich eine beträchtliche vegetabilische Komponente in der Nahrungszusammensetzung der Monte Bibele-Bevölkerung, deren Wirtschaftsweise vorwiegend agrarisch war. Eine diachronische Variation in der Frequenz der untersuchten Zahnmerkmale weist schließlich auf Veränderungen der Ernährung im Verlauf der Zeit hin.

Um zur Aufstellung einer Verteilungskarte des Bf-Polymorphismus in Italien beizutragen, wurden eine Reihe von Populationsstichproben aus verschiedenen Regionen Italiens mit insgesamt 2033 Individuen typisiert. Diese Stichproben stammen aus Bologna, Potenza und Matera, Media Valle del Sangro (Chieti) sowie Nord-, Mittel- und Südsardinien. Es wurde eine neue Typisierungsmethode verwendet, die auf Zelluloseacetatelektrophorese mit Immunofixation und Coomassie Blau-Färbung beruht. Die Ergebnisse lassen deutliche regionale Unterschiede in der Verteilung der Bf-Phänotypenhäufigkeiten und -Allelfrequenzen in Italien erkennen. Bemerkenswert ist u. a. die relativ hohe Bf*S-Frequenz und die geringe Bf*F-Frequenz in Potenza. Die sardischen Stichproben unterscheiden sich klar von denen des italienischen Festlandes. Dies scheint durch die insgesamt geringe Bf*S-Frequenz in Sardinien sowie die außergewöhnlich hohe Frequenz des seltenen Bf*F1-Allels auf dieser Insel bedingt zu sein.

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.

Es werden einige Probleme bezüglich der Untersuchung und Verwendung diskontinuierlicher Schädelmerkmale in der Anthropologie diskutiert. Basierend auf Untersuchungen einer umfangreichen Skelettsammlung aus Siena (Toskana, Italien) sowie auf Literaturdaten werden im einzelnen die Bedeutung von Geschlecht, Alter und Lateralität dieser Merkmale erörtert. Es kann herausgestellt werden, daß Lateralität und Geschlecht getrennt berücksichtigt werden sollten. Das Alter erwachsener Individuen scheint in bezug auf das Auftreten dieser Merkmale keine Rolle zu spielen.

Lifestyle habits, host gene repertoire, and alterations in the intestinal microbiota concur to the development of obesity. A great deal of research has recently been focused on investigating the role gut microbiota plays in the pathogenesis of metabolic dysfunctions and increased adiposity. Altered microbiota can affect host physiology through several pathways, including enhanced energy harvest, and perturbations in immunity, metabolic signaling, and inflammatory pathways. A broad range of “omics” technologies is now available to help decipher the interactions between the host and the gut microbiota at detailed genetic and functional levels. In particular, metabolomics—the comprehensive analysis of metabolite composition of biological fluids and tissues—could provide breakthrough insights into the links among the gut microbiota, host genetic repertoire, and diet during the development and progression of obesity. Here, we briefly review the most insightful findings on the involvement of gut microbiota in the pathogenesis of obesity. We also discuss how metabolomic approaches based on nuclear magnetic resonance spectroscopy could help understand the activity of gut microbiota in relation to obesity, and assess the effects of gut microbiota modulation in the treatment of this condition.

The identification of new binding sites raises the problem of defining their role, if any. At times they are shown to be pharmacological receptors, in a strict sense, as they fulfill certain requirements, and a precise physiological role and function, and an endogenous ligand (neurotransmitter) are discovered. At other times, however, neither a clear physiological role nor an endogenous ligand are found, but the term “receptor” is still used, although it may not be a proper one in the conventional pharmacological sense. Furthermore, no clear intracellular signalling transduction pathway is defined and, as a consequence, it is not possible to determine whether drugs binding to these receptors act as agonists or antagonists. What their structure and biological function are and how they mediate the pharmacological effects of ligands may remain for a long time an enigma. The matter, in any case, is of great interest to researchers of different areas, especially to medicinal chemists who foresee novel potential targets for therapeutic interventions. In this meeting one section is dedicated to two examples of this kind of receptors: imidazoline (I) and sigma (σ) receptors.

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Piperidine (I) is coupled with allyl bromide (II) to give N‐allylpiperidine (III) which reacts with bromine to form the dibromopropylpiperidine (IV).