Halogen bond in high-performance liquid chromatography enantioseparations: Description, features and modelling.

Halogen bond (XB)-driven enantioseparations involve halogen-centred regions of electronic charge depletion (σ-hole) as electrophilic recognition sites. The knowledge in this field is still in its infancy. Indeed, although the influence of halogens on enantioseparation have been often considered, only recently the function of electrophilic halogens (Cl, Br, I) as enantioseparations 'drivers' has been demonstrated by our groups. Further to these studies, in this paper we focus on some unexplored issues. First, as XB-driven chiral recognition mechanisms are at an early stage of comprehension, a theoretical investigation based on a series of 32 molecular dynamic (MD) simulations was performed by using polyhalogenated 4,4'-bipyridines and polysaccharide-based polymers as ligands and receptors, respectively. Enantiomer elution orders (EEOs) were derived from calculations and the theoretical model accounted for some analyte- and chiral stationary phase (CSP)-dependent experimental EEO inversions. Then, the function of halogen-centred σ-holes in competitive systems, presenting also hydrogen bond (HB) centres as recognition sites, was considered. In this regard, Pirkle's enantioseparations of halogenated compounds performed on Whelk-O1 were theoretically re-examined and electrostatic potentials (EPs) associated with both σ-holes on halogens and HB centres were computed and compared. Then, the enantioseparation of halogenated 2-nitro-1-arylethanols was performed on cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) and the influence of halogen substituents on the chromatographic results was evaluated by correlating theoretical and experimental data.

In vitro and in vivo pharmacological characterization of SSD114, a novel GABAB positive allosteric modulator.

Positive allosteric modulators (PAMs) of the GABAB receptor have emerged as a novel approach to the pharmacological manipulation of the GABAB receptor, enhancing the effects of receptor agonists with few side effects. Here, we identified N-cyclohexyl-4-methoxy-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (SSD114) as a new compound with activity as a GABAB PAM in in vitro and in vivo assays. SSD114 potentiated GABA-stimulated [35S]GTPγS binding to native GABAB receptors, whereas it had no effect when used alone. Its effect on GTPγS stimulation was suppressed when GABA-induced activation was blocked with CGP54626, a competitive antagonist of the GABAB receptor. SSD114 failed to potentiate WIN55,212,2-, morphine- and quinpirole-induced [35S]GTPγS binding to cortical and striatal membranes, respectively, indicating that it is a selective GABAB PAM. Increasing SSD114 fixed concentrations induced a leftward shift of the GABA concentration-response curve, enhancing the potency of GABA rather than its efficacy. SSD114 concentration-response curves in the presence of fixed concentrations of GABA (1, 10, and 20µM) revealed a potentiating effect on GABA-stimulated binding of [35S]GTPγS to rat cortical membranes, with EC50 values in the low micromolar range. Bioluminescence resonance energy transfer (BRET) experiments in Chinese Hamster Ovary (CHO)-cells expressing GABAB receptors showed that SSD114 potentiates the GABA inhibition of adenylyl-cyclase mediated by GABAB receptors. Our compound is also effective in vivo potentiating baclofen-induced sedation/hypnosis in mice, with no effect when tested alone. These findings indicate that SSD114, a molecule with a different chemical structure compared to known GABAB PAMs, is a novel GABAB PAM with potential usefulness in the GABAB-receptor research field.

Synthesis and pharmacological characterization of 2-(acylamino)thiophene derivatives as metabolically stable, orally effective, positive allosteric modulators of the GABAB receptor.

Two recently reported hit compounds, COR627 and COR628, underpinned the development of a series of 2-(acylamino)thiophene derivatives. Some of these compounds displayed significant activity in vitro as positive allosteric modulators of the GABAB receptor by potentiating GTPγS stimulation induced by GABA at 2.5 and 25 µM while failing to exhibit intrinsic agonist activity. Compounds were also found to be effective in vivo, potentiating baclofen-induced sedation/hypnosis in DBA mice when administered either intraperitoneally or intragastrically. Although displaying a lower potency in vitro than the reference compound GS39783, the new compounds 6, 10, and 11 exhibited a higher efficacy in vivo: combination of these compounds with a per se nonsedative dose of baclofen resulted in shorter onset and longer duration of the loss of righting reflex in mice. Test compounds showed cytotoxic effects at concentrations comparable to or higher than those of GS39783 or BHF177.

Characterization of COR627 and COR628, two novel positive allosteric modulators of the GABA(B) receptor.

The potential efficacy of GABA(B) receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA(B) receptor agonist baclofen considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA(B) receptor may constitute a novel approach in the pharmacological manipulation of the GABA(B) receptor, leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), which act as GABA(B) PAMs in 1) rat cortical membranes and 2) in vivo assay. Both compounds potentiated GABA- and baclofen-stimulated guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding to native GABA(B) receptors, while producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments [displacement of the GABA(B) receptor antagonist, 3-N-[1-((S)-3,4dichlorophenyl)-ethylaminol]-2-(S)hydroxypropyl cyclo-hexylmethyl phosphinic acid ([(3)H]CGP54626)], both COR627 and COR628 increased the affinity of high- and low-affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of positive allosteric modulatory binding sites of the GABA(B) receptor.

Enantioselective hydrogenation of imines in ionic liquid/carbon dioxide media.

The enantioselective hydrogenation of N-(1-phenylethylidene)aniline using cationic iridium complexes with chiral phosphinooxazoline ligands was studied as a chemical probe to assess the potential of ionic liquid/carbon dioxide (IL/CO2) media for, multiphase catalysis. The biphasic system leads to activation, tuning, and immobilization of the catalyst that would be impossible in classical organic solvent systems or in either of the two unconventional media separately. In particular it is demonstrated that (i) the presence of CO2 can be beneficial or even mandatory for efficient hydrogenation in the IL; (ii) the precursor is activated in the IL by anion exchange allowing one to use in situ catalysts; (iii) the anion of the IL greatly influences the selectivity of the catalyst; (iv) the products are readily isolated from the catalyst solution by CO2 extraction without cross contamination of IL or catalyst; and (v) the IL leads to enhanced stability of the catalyst. These results are corroborated and rationalized on the basis of the physicochemical properties of the biphasic medium and the chemical characteristics of the catalytic systems.

Activation, Tuning, and Immobilization of Homogeneous Catalysts in an Ionic Liquid/Compressed CO2 Continuous-Flow System.

A new immobilization scheme for enantioselective catalysts was developed by using a combination of ionic liquids and compressed CO2 . Under continuous flow conditions, stable conversion and asymmetric induction was achieved over more than 60 h in the enantioselective Ni-catalyzed hydrovinylation of styrene. While the ionic liquid dissolves and activates the organometallic catalyst in a tuneable manner, the presence of compressed CO2 greatly facilitates mass transfer and gives easy access to continuous processes.