Effective receptors for fluoride and acetate ions: synthesis and binding study of pyrrole- and cystine-based cyclopeptido-mimetics

Two conformationally constrained pseudo-cyclopeptides (1, 2) consisting of pyrrole-, pyridine-, and cystine-moieties were designed and synthesized as neutral receptors for anionic guests. The anion recognition abilities of these two receptors were examined photometrically in acetonitrile solution. The UV-vis study revealed that the [1+1] receptor (1) formed 1:1 complexes with anions, whereas the [2+2] receptor (2) led to 1:2 mode binding with anions. Both receptors displayed good affinity and selectivity for fluoride and acetate ions.     

Anion selectivity in zwitterionic amide-functionalised metal salt extractants

Amide-functionalised salen ligands capable of extracting metal salts have been synthesised and characterised. Single-crystal X-ray structure determinations of complexes of NiSO4, [Ni(L)(SO4)], confirm that the ionophores are in a zwitterionic form with Ni(II) bound in the deprotonated salen moiety and the SO4(2-) ion associated with protonated pendant N'-amidopiperazine groups. Treatment of [Ni(L)(SO4)] with base removes the protons from the pendant amido-amine group resulting in loss of the SO4(2-) ion and formation of metal-only complexes of type [Ni(L-2H)], which have been characterized by single-crystal X-ray diffraction. Three of the ligands with solubilities suitable for solvent extraction studies show loading and stripping pH-profiles that are suitable for the recovery of CuSO4 or CuCl2 from industrial leach solutions. The copper-only complexes, [Cu(L-2H)], are selective for Cl- over SO4(2-) in both solvent extraction and bulk liquid membrane transport experiments and were found to bind Cl- in two steps via the formation of a 1:1:1 [Cu(L-H)Cl] assembly, followed by a 1:1:2 [Cu(L)Cl2] assembly as the pH of the aqueous phase is lowered. The anion transport selectivity was evaluated for a number of other mono-charged anions and interestingly the ligands were found to display a preference for the Br- ion. To probe the influence of the Hofmeister bias on the selectivity of anion complexation, single-phase potentiometric titration experiments were employed to investigate the binding of SO4(2-) and Cl- by one of the copper only complexes, [Cu(L-2H)] in 95 %/5 % MeOH/water. Under these conditions selectivity was reversed (SO4(2-)>Cl-) confirming that the Hofmeister bias, which reflects the relative hydration energies of the anions, dominates the selectivity of anion extraction from aqueous media into CHCl3.     

How Important Is Molecular Rigidity for the Complex Stability of Artificial Host–Guest Systems? A Theoretical Study on Self‐Assembly of Gas‐Phase Arginine

Arginine forms much less stable dimers than 2-(guanidiniocarbonyl)-1H-pyrrole-5-carboxylate although the principal binding interactions are very similar. The reasons for this difference are addressed in this work by state-of-the-art ab initio computations. The investigation shows that the extraordinary high stability of the 2-(guanidiniocarbonyl)-1H-pyrrole-5-carboxylate dimer results to about 50 % from the rigidity of its monomer. Within this study monomer and dimer conformers of arginine were calculated leading to new low lying structures which have not been reported before as well as new global minima are predicted. In these structures stacking interactions with the guanidinium moiety are especially important. For the monomer we predict the energy minimum to be the canonical form with the lowest lying zwitterionic structure being only 9 kJ mol(-1) less stable. During the course of these calculations we found that DFT did not predict the structures and their relative energy correctly in comparison to perturbation theory (MP2) and some potential reasons for the failure of DFT in these cases are discussed. Vibrational frequencies of the various structures are presented and a suitable wavenumber region for an experimental determination of the global minimum of the arginine monomer is identified. The effect of molecular rigidity on the self-assembly is probed using a local minimum of the arginine monomer which does not possess any intramolecular stabilizing effects. Our results suggest that the deliberate control of the conformational flexibility is a powerful instrument to steer the complex affinity of artificial hosts.     

Extraction of radio-labelled xanthine derivatives by artificial receptors: deep insight into the association behaviour

Association constants for the interaction of almost insoluble substrates with triphenylene ketal-based receptors in toluene have been determined by means of an extraction method employing the corresponding radio-labelled substrates. Flexible and more polar receptors tend to aggregate and exhibit inferior extraction qualities. Binding constants in toluene were found to be in the range 10(5)-10(7) m(-1), which is significantly higher than in dichloromethane. X-ray analyses indicate the direct participation of a water molecule in the binding process, which may account for the surprisingly small effect of moisture in the solvent on the stability of the complexes.     

The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α_1A/α_1D affinity and selectivity towards α_1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.     

Effect of Intrahippocampal Administration of α7 Subtype Nicotinic Receptor Agonist PNU-282987 and Its Solvent Dimethyl Sulfoxide on the Efficiency of Hypoxic Preconditioning in Rats

We have previously suggested a key role of the hippocampus in the preconditioning action of moderate hypobaric hypoxia (HBH). The preconditioning efficiency of HBH is associated with acoustic startle prepulse inhibition (PPI). In rats with PPI > 40%, HBH activates the cholinergic projections of hippocampus, and PNU-282987, a selective agonist of α7 nicotinic receptors (α7nAChRs), reduces the HBH efficiency and potentiating effect on HBH of its solvent dimethyl sulfoxide (DMSO, anticholinesterase agent) when administered intraperitoneally. In order to validate the hippocampus as a key structure in the mechanism of hypoxic preconditioning and research a significance of α7nAChR activation in the hypoxic preconditioning, we performed an in vivo pharmacological study of intrahippocampal injections of PNU-282987 into the CA1 area on HBH efficiency in rats with PPI ≥ 40%. We found that PNU-282987 (30 μM) reduced HBH efficiency as with intraperitoneal administration, while DMSO (0.05%) still potentiated this effect. Thus, direct evidence of the key role of the hippocampus in the preconditioning effect of HBH and some details of this mechanism were obtained in rats with PPI ≥ 40%. The activation of α7nAChRs is not involved in the cholinergic signaling initiated by HBH or DMSO via any route of administration. Possible ways of the potentiating action of DMSO on HBH efficiency and its dependence on α7nAChRs are discussed.