WLB-87848, a Selective σ Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3-]pyrimidin-4(3)-one derivatives as sigma-1 receptor (σR) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σR agonist () that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σR. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σR association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making (WLB-87848) an interesting candidate for neuroprotection.

Discovery of WLB-89462, a New Drug-like and Highly Selective σ Receptor Ligand with Neuroprotective Properties.

The synthesis and pharmacological activity of a new series of isoxazolylpyrimidines as sigma-2 receptor (σR) ligands are reported. Modification of a new hit retrieved in an HTS campaign allowed the identification of the compound WLB-89462 () with good σR affinity ( = 13 nM) and high selectivity vs both the σR ( = 1777 nM) and a general panel of 180 targets. It represents one of the first σR ligands with drug-like properties, linked to a good physicochemical and ADMET profile (good solubility, no CYP inhibition, good metabolic stability, high permeability, brain penetration, and high oral exposure in rodents).

Propionamide Derivatives as Dual μ-Opioid Receptor Agonists and σ Receptor Antagonists for the Treatment of Pain.

A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, , showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.

Synthesis and structure-activity relationship study of a new series of selective σ(1) receptor ligands for the treatment of pain: 4-aminotriazoles.

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ1 receptor (σ1R) ligands are reported. The compounds were prepared using a 4-5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ1R, and the selectivity over the σ2R was improved on decreasing the central amine basicity.

Synthesis and biological evaluation of a new series of hexahydro-2H-pyrano[3,2-c]quinolines as novel selective σ1 receptor ligands.

The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores.

Studies on the amination of aryl chlorides with a monoligated palladium catalyst: kinetic evidence for a cooperative mechanism.

Combined spectroscopic, crystallographic, and kinetic studies of the mechanism of aromatic amination with the efficient dinuclear Pd precatalyst [Pd(2)Cl(μ-Cl)PtBu(2)(Bph-Me)] (Bph-Me = 2'-methyl-[1,1'-biphenyl]-2-yl) have revealed overlapping, yet cooperative, mechanistic scenarios, the relative weights of which are strongly influenced by the products formed as the reaction proceeds. The stability and evolution of the precatalyst in solution has been studied and several metalation pathways that point to a single monoligated intermediate have been identified. Our work sheds light on the nature of the catalytic species involved in the process and on the structure of the corresponding catalytic network.

Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862).

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores.

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.

Experimental and theoretical investigations of new dinuclear palladium complexes as precatalysts for the amination of aryl chlorides.

A series of new palladium dinuclear species with general formula [Pd2X(mu-X)[mu-P(t)Bu2(Bph-R)]] (X = Cl, Br; Bph = biphenyl; R = H, Me, NMe2) have been prepared. The two palladium centers in these species are bridged by one of the aromatic rings of the biphenyl group present in the corresponding phosphine. The X-ray crystal structure of one of these complexes has been obtained, providing a clear picture of the bonding pattern.

Monoligated palladium species as catalysts in cross-coupling reactions.

Palladium-mediated cross-coupling reactions are attractive organometallic transformations for the generation of C--C, C--N, C--O, and C--S bonds. Despite being widely employed in small-scale syntheses, cross-coupling reactions have not found important industrial applications because until recently, only reactive aryl bromides and iodides could be used as substrates. These substrates are generally more expensive and less widely available than their chloride counterparts.

Substrate binding to vanadate-dependent bromoperoxidase from Ascophyllum nodosum: a vanadium K-edge XAS approach.

The EXAFS region of vanadium K-edge XAS spectra of native vanadate-dependent bromoperoxidase (isoenzyme I) from Ascophyllum nodosum in the presence of the substrate bromide can be fitted to three shells (at 1.62, 1.73-1.