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Many known 5-HT7 ligands contain either a serotonin-like or an arylpiperazine structure that, in published SAR studies, are generally supposed to bind the same receptor pocket. Conversely, we explored the hypothesis that two such moieties can co-exist in the same ligand, binding to different pockets. We thus designed and synthesized a set of compounds including both a 5-hydroxyindol-3-ylethyl and a 1-arylpiperazine moieties connected by a short linker. The compounds were tested for their affinity for human 5-HT7 serotonin receptor. We further prepared a novel series of 5-HT7 ligands, where the 5-hydroxyindol-3-ylethyl moiety was bioisosterically replaced by a 3-hydroxyanilinoalkyl one. Among the newly synthesized compounds, potent ligands at the 5-HT7 receptor, behaving as antagonists in functional tests, were identified, even if they showed limited subtype selectivity. Docking studies within a model of the 5-HT7 receptor showed that the binding site can actually accommodate both moieties, with the serotonin-like one in the putative orthosteric site and the arylpiperazine one occupying an accessory pocket. The present results demonstrate that it is possible to devise and develop new 5-HT7 ligands merging two privileged structures in the same molecule.

Melatonin (MLT) is a neurohormone implicated in several physiological processes such as sleep. Contrasting results have been produced on whether or not it may act as a hypnotic agent, and the neurobiological mechanism through which it controls the vigilance states has not yet been elucidated. In this study we investigated the effect of MLT (40 mg/kg), a non-selective MT1/MT2 receptor agonist (UCM793, 40 mg/kg), and a selective MT2 partial agonist (UCM924, 40 mg/kg) on the 24-h vigilance states. EEG and EMG sleep-wake patterns were registered across the 24-h light-dark cycle in adult Sprague-Dawley male rats. MLT decreased (-37%) the latency to the first episode of non rapid eye movement sleep (NREMS), enhanced the power of NREMS delta band (+33%), but did not alter the duration of any of the three vigilance states. Differently, UCM793 increased the number of episodes (+52%) and decreased the length of the episodes (-38%) of wakefulness but did not alter the 24-h duration of wakefulness, NREMS and REMS. UCM924 instead reduced the latency (-56%) and increased (+31%) the duration of NREMS. Moreover, it raised the number of REMS episodes (+57%) but did not affect REMS duration. Taken together, these findings show that MLT and non-selective MT1/MT2 receptor agonists do not increase the quantity of sleep but differently influence the three vigilance states. In addition, they support the evidence that selective MT2 receptor agonists increase NREMS duration compared to MLT and non-selective MT1/MT2 agonists.

We report the synthesis, binding properties and intrinsic activity at MT(1) and MT(2) melatonin receptors of new dimeric melatonin receptor ligands in which two units of the monomeric agonist N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (1) are linked together through different anchor points. Dimerization of compound 1 through the methoxy substituent leads to a substantial improvement in selectivity for the MT(1) receptor, and to a partial agonist behavior. Compound 3a, with a trimethylene linker, was the most selective for the MT(1) subtype (112-fold selectivity) and compound 3d, characterized by a hexamethylene spacer, had the highest MT(1) binding affinity (pK(iMT1)=8.47) and 54-fold MT(1)-selectivity. Dimerization through the aniline nitrogen of 1 abolished MT(1) selectivity, leading to compounds with either a full agonist or an antagonist behavior depending on the nature of the linker.

Melatonin is a modified tryptophan with potent biological activity, exerted by stimulation of specific plasma membrane (MT1/MT2) receptors, by lower affinity intracellular enzymatic targets (quinone reductase, calmodulin), or through its strong anti-oxidant ability. Scattered studies also report a perplexing pro-oxidant activity, showing that melatonin is able to stimulate production of intracellular reactive oxygen species (ROS). Here we show that on U937 human monocytes melatonin promotes intracellular ROS in a fast (

New penicillin, penicillin sulfone and sulfoxide derivatives bearing a C-6-alkyliden substituent were prepared. Their chemical synthesis, in vitro antibacterial activity and inhibition properties against two selected enzymes representing Class A and C β-lactamases are reported. Compounds 3a – c , 7a – c were able to inhibit either TEM-1 (a Class A enzyme, from Escherichia coli ) or P-99 (a Class C enzyme, from E. cloacae ), or both enzymes, when tested in competition experiments using nitrocefin as the reporter substrate. However, when tested in combination with amoxicillin, the same compounds did not show synergistic effects against E. coli and E. cloacae strains producing TEM-1 and P99 enzymes, respectively. This finding is most likely related to poor penetration through the bacterial cell wall, as shown by using a more permeable isogenic E. coli strain. Interestingly, a synergistic effect against a strain of S. aureus which produces PC1-enzyme (a Class A β-lactamase) was observed for compound 3a when used in combination with amoxicillin.

A number of 6-methoxy-1-(2-propionylaminoethyl)indoles, carrying properly selected substituents at the C-2 indole position, were prepared and tested as melatonin receptor ligands. Affinities and intrinsic activities for the human cloned mt 1 and MT 2 receptors were examined and compared with those of some 2-substituted melatonin derivatives recently described by us. A quantitative structure–activity relationship (QSAR) study of the sixteen 2-substituted indole compounds, 5a – k , 1 , 8 – 11 , using partial least squares (PLS) and multiple regression analysis (MRA) revealed the existence of an optimal range of lipophilicity for the C-2 indole substituent. There are also indications that planar, electron-withdrawing substituents contribute to the affinity by establishing additional interactions with the binding pocket. No mt 1 /MT 2 subtype selectivity was observed, with the relevant exception of the 2-phenethyl derivative 5e , which exhibited the highest selectivity for the h-MT 2 receptor among all the compounds tested (MT 2 /mt 1 ratio of ca. 50). Conformational analysis and superposition of 5e to other reported selective MT 2 ligands revealed structural and conformational similarities that might account for the MT 2 /mt 1 selectivity of 5e .

Twenty 4,5-dimethylpyrrole-2-carboxylic acids (5a-t) with different 2-carbamoylvinyl chains in position 3 were prepared to further investigate the relationships between structure and in vitro affinity for the strychnine-insensitive glycine-binding site. None of these compounds was superior to (E)-3-(N-phenyl-2-carbamoylvinyl)-4,5-dimethylpyrrole-2-carb oxylic acid III (pKi = 6.70), which was taken as a reference standard, but overall the results obtained indicate that the N-phenyl-2-carbamoylvinyl substituent of III may be replaced with the N-(1-adamantyl)-2-carbamoylvinyl group as in 5h (pKi = 6.20) without considerable loss of affinity. This finding adds to previous knowledge.

The reactivity and in particular the siteselectivity of [3+2] electrocyclic additions to 1,1-diphenyl-2-aza -1,3-butadienes, substituted or not on the terminal carbon with methyl and phenyl, and with a 3-carbomethoxyl group, have been investigated with the 1,3-dipolar reagents 4-nitrobenzonitrile oxide and diazomethane. The role of the 3-carbomethoxy substituent in determining the siteselectivity observed in these reactions is discussed in relation to experimental results and to conformational models of some of the tested 2-azadiene dipolarophiles calculated on AM1 bases.

The reactions of 1,1-diphenyl-3-carbomethoxy-2-aza-1,3-butadiene derivatives la - e (on C4 : H,H or H,CH 3 or H,C 6 H 5 , both E and Z isomers), and of the C4 unsubstituted 1 -phenyl-1-ethoxy analogue 2, were studied with a number of electron-rich and electron-poor dienophiles, with results showing that la - e give heterocycloadducts in Diels-Alder reactions with electron-poor dienophiles. Michael adducts were obtained from the EtAlCl 2 catalyzed reactions of these compounds with dimethyl acetylendicarboxylate. Compound 2 gave heterocyclic adducts as well but behaved like a nucleophile, at least in the case of the reactions with dimethyl acetylendicarboxylate and ethyl propynoate: these reactions afforded 2-azatrienes as Michael adducts that gave pyridine derivatives upon heating. The synthesis of the new 1-ethoxy-2-aza-1,3-butadiene 2 is also reported.

Chemical ionisation in ammonia and in methane, electron impact ionisation and mass selected collision induced dissociation involving 10 1-aminocyclopropane- 1 -carboxylic acid derivatives are reported. The data presented, exhibit a number of qualitative differences which are attributed to the different isomeric structures of the investigated precursors. Competition between protonation and addition reaction channels which yield MH+ and [M + NH4]+ in ammonia, chemical ionisation and the different internal excitation experienced by ions formed in chemical ionisation, and by electron impact, are two experimental observations which the present work seeks to underline.