Tricyclic Triazoles as σ1 Receptor Antagonists for Treating Pain.

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, 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 (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-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-5H-pyrimido[4,5-e][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. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.

Determination of choline and derivatives with a solid-contact ion-selective electrode based on octaamide cavitand and carbon nanotubes.

A new solid-contact ion-selective electrode has been developed for determining choline and derivatives in aqueous solutions. The backbone of this new potentiometric sensor is the conjunction of the cavitand receptor, as the molecular recognition element, and a network of non-carboxylated single-walled carbon nanotubes, acting as a solid transducer material. The octaamide cavitand, a synthetic receptor that is highly selective for biologically important trimethyl alkylammonium cations such as choline, acetylcholine or carnitine, makes the selective determination of these compounds possible for the first time. The guest-host interaction takes place in the acrylate ion-selective membrane of the solid-contact electrode. The sensor was characterized by electrochemical impedance spectroscopy and environmental scanning electron microscopy. The new electrode displays a nearly Nernstian slope (57.3+/-1.0 mV/decade) and very stable behaviour (DeltaE/Deltat=224 muVh(-1)) throughout the dynamic range (10(-5) to 10(-1)M). The limit of detection of 10(-6.4)M and the high selectivities obtained will enable choline and derivatives to be determined in biological samples. Finally, the stability of the electrical potential of the new solid-contact electrode was examined by performing current-reversal chronopotentiometry and the influence of the interfacial water film was evaluated by the potentiometric water layer test.

A combined experimental and theoretical study of the molecular inclusion of organometallic sandwich complexes in a cavitand receptor.

We describe herein a detailed study of the inclusion processes of several positively charged organometallic sandwich complexes inside the aromatic cavity of the self-folding octaamide cavitand 1. In all cases, the binding process produces aggregates with a simple 1:1 stoichiometry. The resulting inclusion complexes are not only thermodynamically stable, but also kinetically stable on the (1)H NMR spectroscopy timescale. The binding constants for the inclusion complexes were determined by different titration techniques. We have also investigated the kinetics of the binding process and the motion of the metallocenes included in the aromatic cavity of the host. Using DFT-based calculations, we have evaluated the energies of a diverse range of potential binding geometries for the complexes. We then computed the proton chemical shifts of the included guest in each one of the binding geometries. The agreement between the averaged computed values and the experimentally determined chemical shifts clearly supports the proposed binding geometries that we assigned to the inclusion complexes formed in solution. The combination of experimental and theoretical results has allowed us to elucidate the origins of the distinct features detected in the complexation process of the different guests, as well as their different motions inside the host.

Hybrid cavitand-resorcin[4]arene receptor for the selective binding of choline and related compounds in protic media.

[structure: see text] A hybrid cavitand-resorcin[4]arene receptor capable of displaying pH-modulated binding affinity toward trimethylalkylammonium ions is proposed as an alternative to the low selectivity exhibited by other receptors used in supramolecular fluorescent sensor systems for choline.

Regio- and stereospecific cleavage of silyl- and disilylepoxides with lithium diphenylphosphide.

Unsubstituted or alpha- and beta-C-substituted silylepoxides react stereospecifically with lithium diphenylphosphide, optionally followed by methylation, to give vinylphosphonium iodides or vinylphosphine oxides resulting from alpha-opening and silyl enol ethers, vinylsilanes or alpha-hydroxysilanes by beta-opening. On the other hand, alpha,beta- or alpha,alpha-disilylepoxides afforded beta-silyl vinylphosphine oxides or alpha-silylated silyl enol ethers by alpha- and beta-cleavage, respectively. All compounds are interesting synthons in organic chemistry.