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.

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.

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.

Molecular inclusion of organometallic sandwich complexes within hybrid cavitand-resorcin[4]arene receptors.

Two different hybrid cavitand-resorcin[4]arenes are shown to be effective and selective receptors for the molecular inclusion of positively charged organometallic sandwich complexes of appropriate size. The binding constants of the 1 : 1 complexes formed with a series of neutral and positively charged metallocenes have been calculated using different titration techniques. The motion of the included metallocene and the kinetics of the complexation process are investigated.

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.