Tricyclic Triazoles as σ Receptor Antagonists for Treating Pain.

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4,6-pyrrolo[3,4-][1,2,3]triazolo[1,5-][1,4]oxazine derivatives as potent sigma-1 receptor (σR) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σR antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic p (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, and , exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter.

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Caα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Caα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5-pyrimido[4,5-][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality.

Highly active organocatalysts for asymmetric anti-Mannich reactions.

Lighten the load! A family of enantiopure 4-oxy-substituted 3-aminopyrrolidines arising from the enantioselective ring-opening of meso-3-pyrroline oxide have been developed as catalysts for the asymmetric, anti-selective Mannich reaction (see scheme; PMP=p-methoxyphenyl; PG=protecting group). Very high catalytic activity (down to 0.01 mol % loading) and stereoselectivity have been recorded.

Intramolecular azide-alkyne cycloaddition for the fast assembly of structurally diverse, tricyclic 1,2,3-triazoles.

The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure compounds is also reported. Some of these compounds exhibit significant affinity for the sigma-1 receptor.

Structurally simple, modular amino alcohols for the recognition of carboxylic acids. Application to the development of a new chiral solvating agent.

[structure: see text] Two flexible receptors for carboxylic acids, based on 1-amino-3-fluoro-2-alcohol functional arrays and built on aminomethylpyridine platforms, are described. The C(2)-symmetric one [from 2,6-bis(aminomethyl)pyridine] has been shown to be an efficient CSA due to its ability to form geometrically different diastereomeric complexes enabling the discrimination between the enantiomers of a series of carboxylic acid in the (1)H NMR spectra.

Design and synthesis of inositolphosphoglycan putative insulin mediators.

The binding modes of a series of molecules, containing the glucosamine (1-->6) myo-inositol structural motif, into the ATP binding site of the catalytic subunit of cAMP-dependent protein kinase (PKA) have been analysed using molecular docking. These calculations predict that the presence of a phosphate group at the non-reducing end in pseudodisaccharide and pseudotrisaccharide structures properly orientate the molecule into the binding site and that pseudotrisaccharide structures present the best shape complementarity. Therefore, pseudodisaccharides and pseudotrisaccharides have been synthesised from common intermediates using effective synthetic strategies.

Synthesis, conformational analysis, and cytotoxicity of conformationally constrained aplidine and tamandarin A analogues incorporating a spirolactam beta-turn mimetic.

With the aim of studying the contribution of the beta II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro8-N-Me-d-Leu7 is replaced with the spirolactam beta II turn mimetic (5R)-7-[(1R)-1-carbonyl-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl9) or tamandarin A [(S)-Lac9] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared.

A Synthetic Cation-Transporting Calix[4]arene Derivative Active in Phospholipid Bilayers.

One order of magnitude: The transport of Na and K ions through a phospholipid bilayer occurs with much higher conductance levels with 1 and 2 than with typical Na -transporting proteins or gramicidin. However, the cations do not appear to pass through the calix[4]arene ring, which has a rigid 1,3-alternate conformation. diazacrown=10-benyzl-1,10-diaza[18]crown-6 group.