Glycine Ligands Research Articles

Bis{N-[2-hy-droxy-1,1-bis-(hy-droxy-methyl)eth-yl]glycinato-κ(3) O,N,O'}iron(II).

In the title compound, [Fe(C6H12NO5)2], the FeII ion lies on an inversion center and is coordinated by two N atoms and four O atoms from two tridentate N-[2-hy­droxy-1,1-bis­(hy­droxy­methyl)eth­yl]glycine ligands, forming a slightly distorted octa­hedral coordination environment. In the crystal, O—H⋯O, O—H⋯N and weak C—H⋯O hydrogen bonds link mol­ecules, forming a three-dimensional network.

Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options.

The negative symptoms of schizophrenia represent an impairment of normal emotional responses, thought processes and behaviors, and include blunting or flattening of affect, alogia/aprosody, avolition/apathy, anhedonia, and asociality. Negative symptoms contribute to a reduced quality of life, increased functional disability, increased burden of illness, and poorer long-term outcomes, to a greater degree than positive symptoms. Primary negative symptoms are prominent and persistent in up to 26% of patients with schizophrenia, and they are estimated to occur in up to 58% of outpatients at any given time. Negative symptoms respond less well to medications than positive symptoms, and to date treatment options for negative symptoms have been limited, with no accepted standard treatment. Modest benefits have been reported with a variety of different agents, including second-generation antipsychotics and add-on therapy with antidepressants and other pharmacological classes. Recent clinical research focusing on negative symptoms target novel biological systems, such as glutamatergic neurotransmission. Different approaches include: enhancing N-methyl-D-aspartate receptor function with agents that bind directly to the glycine ligand site or with glycine reuptake inhibitors; influencing the metabotropic glutamate receptor (mGluR2/3) with positive allosteric modulators; and stimulating nicotinic acetylcholine receptors. In conclusion, the lack of clearly efficacious pharmacological treatments for the management of negative symptoms represents a significant unmet need, especially considering the importance of these symptoms on patient outcomes. Hence, further research to identify and characterize novel pharmacological treatments for negative symptoms is greatly needed.

Use of Charge-Assisted Hydrogen Bonding in the Supramolecular Assembly of Hybrid Uranyl Materials

Supramolecular assembly of U(VI) materials can be limited by the passivation of the uranyl oxo group and the propensity of the metal center to hydrolyze, resulting in the formation of extended two-dimensional (2D) structures. To overcome these barriers, the use of charge-assisted H-bonding was explored using amino acids (glycine [Gly] and l-alanine [Ala]), resulting in the formation of three novel compounds {[(UO2)3(Gly)2(O)2(OH)2](H2O)6 (1), [(UO2)5(Gly)4(O)3(OH)3](NO3)(H2O)12 (2), and [(UO2)3(Ala)2O(OH)3](NO3)(H2O)3 (3)} that have been characterized by X-ray diffraction, elemental analysis, TGA, and vibrational spectroscopy. Hydrolysis of the uranyl cation (UO22+) chelated by bridging zwitterionic amino acids results in the formation of infinite chains when synthesized from mildly acidic aqueous solutions. While positively charged chains form densely packed structures, the neutral UO2-glycine chains support a nanoporous (internal diameter ∼1.35 nm) supramolecular architecture through multifurcated charge-assisted hydrogen bonding. These interactions occur directly between the protonated amine of glycine and the uranyl’s oxo moiety, representing a unique supramolecular synthon for the assembly of hybrid porous uranyl materials. The zwitterionic glycine ligands also assist in the helical assembly of water molecules that are hydrogen bonded to the interior walls of the nanopores, resulting in the formation of an empty 0.85 nm channel through the pore space.

Dinuclear copper(II) complexes hold by crab-shaped pincer ligands: Syntheses, structures, luminescent and magnetic properties

Two Cu(II) complexes with N,N′-(2-hydroxy-5-R-1,3-xylylene)bis(N-(carboxymethyl)glycine (R-H5XTA, R=Cl and Br) ligands have been synthesized and their crystal structures have been analyzed by X-ray diffraction methods. The ligands provide a convenient dinucleating feature with the phenolate oxygen providing the bridging function. The complexes consist of dinuclear copper units, hexahydrate copper ion and solvent water molecules. Thereinto, dimer copper ions show two different geometries as Cu1 distorted octahedron and Cu2 square-based pyramid respectively, which has been confirmed by the solid-state electronic absorption spectrum. The thermal decomposition process consists of the loss of corresponding water molecules below 473K and follow-up decomposition of the main structures. Under the excitation of 360nm light, luminescence of ligands is quenched by the coordinated Cu(II) ions and heavy Br atom, respectively. Magnetic study shows that coupling of dinuclear copper ions displays ferromagnetic behavior with the J=+9.03cm−1.

Thermal decomposition and biological activity studies of some transition metal complexes derived from mixed ligands sparfloxacin and glycine

The synthetic method of novel ternary M(II)/(III)/(IV) complexes, with fluoroquinolone drug sparfloxacin (HSFX) and glycine (HGly) containing nitrogen and oxygen donor ligand have been synthesized and characterized. The prepared complexes fall into stoichiometric formulae of [M(SFX)(Gly)(H2O)2]Cl (M = Cr(III) and Fe(III), [M(SFX)(Gly)(H2O)2] (M = Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and UO2(II) and [Th(SFX)(Gly)(H2O)2]Cl2. The chelate rings are six-membered and six coordinate with 1:1:1 [M]:[SFX]:[Gly]. The important bands in the IR Spectra and main 1H NMR signals are tentatively assigned and discussed in relation to the predicted molecular structure. The IR data of the HSFX and HGly ligands suggested the existing of a bidentate binding involving carboxylate O and carbonyl O for HSFX ligand and amino N and carboxylate O atoms for HGly ligand. The coordination geometries and electronic structures are determined from the diffused reflectance spectra and magnetic moment measurements. The complexes exist in octahedral form. The complexes decomposed in four to six steps within the temperature range 30–1,000 °C with metal oxides as residues of decomposition. The decomposition steps are accompanied by endothermic or exothermic peaks in the DTA. The HSFX drug, HGly and metal complexes have been screened for their in vitro antibacterial activities against Staphylococcus aureus and Escherichia coli, and antifungal activities against Aspergillus niger and Candida albicans by MIC method. The metal complexes were found to have higher antimicrobial activity than the HSFX drug and HGly ligand and their activity are comparable with the antibacterial and antifungal standards.

Seven-, eight-, and ten-coordinated cerium(III) with highly connective pyridine-2,4,6-tricarboxylate, oxalate, and glycine ligands

Two new 3-D Ce(III) coordination polymers, [Ce1.3(PTA)2(Oxa)2(Gly)(H2O)2]·(Gly)4H2O (1) and [Ce2.6(PTA)4(Oxa)2(H2O)10]·(MeOH)7H2O (2) (PTA = 2,4,6-pyridinetricarboxylate, oxa = oxalate and Gly = glycine), were synthesized. The oxalate in 1 and 2, generated in situ from the cleavage and chemical rearrangement of PTAH3, assembled into mixed-ligand networks to generate 3-D frameworks. Single crystal analysis reveals that in both complexes, Ce(III) shows coordination numbers of 7 and 10 in 1 and 8 and 10 in 2. PTA adopts four kinds of coordination modes. These complexes were further characterized using elemental analysis, FTIR spectroscopy and thermogravimetric analysis.

Plutonium(IV) Cluster with a Hexanuclear [Pu6(OH)4O4]12+ Core

A mixed hydroxo/oxo plutonium(IV) carboxylate resulting from the hydrolysis and condensation of Pu(IV) in an acidic aqueous solution has been isolated. The structure of Li6[Pu6(OH)4O4(H2O)6(HGly)12]Cl18·10.5H2O (1) consists of a cationic [Pu6(OH)4O4](12+) core that is decorated by glycine ligands. The synthesis, structure, and characterization of the hexanuclear unit, which represents the first example of a Pu(IV) polynuclear complex containing both hydroxo- and oxo-bridging ligands, are described herein.

Synthesis and Crystal Structure of Tetranuclear Nickel Complex Derived from a N-(3-Methoxy-2-hydroxybenzyl)glycine Ligand

Synthesis and Crystal Structure of Tetranuclear Nickel Complex Derived from a N-(3-Methoxy-2-hydroxybenzyl)glycine Ligand

Estimation of absorption of magnesium nicotinate and its derivatives with selected amino acids

Preparation of solid dispersions is a popular pharmaceutical technology designed to improve the solubility and absorption characteristics of drugs. Solubilizing and moisturizing of carriers show influence on therapeutic substances; although dissolution of molecular dispersion of particles of the therapeutic substance in a neutral carrier is of utmost importance. This paper present the results of the research on influence of modification the structure of magnesium nicotinate Mg(Nic) with ligands, glycine and arginine, on the absorption process of Mg 2+ ions in vitro. The absorption area was the small intestine of a rat. It was found that structural changes with an additional arginine or glycine ligand affect the absorption process of Mg 2+ ions. Moreover, the effect of hydrophilic carriers on the partition coefficient (log P) for the system of n-octanol and phosphate buffer was investigated for the solid dispersions containing the examined magnesium salts. Phosphatidylcholine (PC-45) and polyvinylpirrolidone (PVP K-30) were used as carriers for solid dispersions with of magnesium salts. It was confirmed that using auxiliary substances PC-45 and PVP changes significantly (p<0.05) P values, corresponding to increasing hydrophobic properties of solid dispersions of the examined salts. It was found that modification of the structure of magnesium nicotinate by amino acids such as arginine or glycine positively influences the absorption process Mg 2+ ions. The research carried out on properties of the solid dispersions containing magnesium salts and phospatidylcholine (PC-45) or magnesium salts and polyvinylpirrolidone (PVP K30) showed positive influence of these auxiliary substances.

Biological and cytoselective anticancer properties of copper(II)-polypyridyl complexes modulated by auxiliary methylated glycine ligand

A series of ternary copper(II)-1,10-phenanthroline complexes with glycine and methylated glycine derivatives, [Cu(phen)(aa)(H(2)O)]NO(3)·xH(2)O 1-4 (amino acid (aa): glycine (gly), 1; DL: -alanine (DL: -ala), 2; 2,2-dimethylglycine (C-dmg), 3; sarcosine (sar), 4), were synthesized and characterized by FTIR, elemental analysis, electrospray ionization-mass spectra (ESI-MS), UV-visible spectroscopy and molar conductivity measurement. The determined X-ray crystallographic structures of 2 and 3 show each to consist of distorted square pyramidal [Cu(phen)(aa)(H(2)O)](+) cation, a nitrate counter anion, and with or without lattice water, similar to previously reported structure of [Cu(phen)(gly)(H(2)O)]NO(3)·1½H(2)O. It is found that 1-4 exist as 1:1 electrolytes in aqueous solution, and the cationic copper(II) complexes are at least stable up to 24h. Positive-ion ESI-MS spectra show existence of only undissociated [Cu(phen)(aa)](+) species. Electron paramagnetic resonance, gel electrophoresis, fluorescence quenching, and restriction enzyme inhibition assay were used to study the binding interaction, binding affinity and selectivity of these complexes for various types of B-form DNA duplexes and G-quadruplex. All complexes can bind selectively to DNA by intercalation and electrostatic forces, and inhibit topoisomerase I. The effect of the methyl substituents of the coordinated amino acid in the above complexes on these biological properties are presented and discussed. The IC(50) values (24h) of 1-4 for nasopharyngeal cancer cell line HK1 are in the range 2.2-5.2μM while the corresponding values for normal cell line NP69 are greater than 13.0μM. All complexes, at 5μM, induced 41-60% apoptotic cell death in HK1 cells but no significant cell death in NP69 cells.

Synthesis and structural characterization of a calcium coordination polymer based on a μ 3 -bridging tetradentate binding mode of glycine#

A new coordination polymer namely [[Ca6(H–gly)12(H2O)18]Cl12·6H2O]n (1) (H–gly = glycine) has been isolated from the calcium chloride–glycine–water system and structurally characterized. Each Ca(II) in 1 is eight-coordinated and is bonded to eight oxygen atoms three of which are from terminal water molecules and five oxygen atoms from four symmetry related zwitterionic glycine ligands. The H–gly ligands exhibit two different binding modes viz. a monodentate carboxylate ligation and a μ3-tetradentate bridging carboxylate binding mode, which results in the formation of a one-dimensional coordination polymer. In the infinite chain the Ca(II) atoms are organized in a zigzag fashion. A comparative study reveals a rich and diverse structural chemistry of calcium halide–glycine compounds. The synthesis and structural characterization of a new coordination polymer namely [[Ca6(H–gly)12(H2O)18]Cl12·6H2O]n (1) (H-gly = glycine) isolated from the calcium chloride–glycine–water system is reported.

The determination of the stability constants of complexes of 1,2,4-triazoles and biologically relevant ligands with M(II) by potentiometric titration in aqueous solution

Potentiometric equilibrium measurements have been performed at 25 ± 0.1°C and I = 0.10 mol dm−3 NaNO3 for the interaction of 1,2,4-triazole and M(II) [Cu, Co, Ni, and Zn] with some biologically important ligands (glycine, α-alanine, DL-valine, n-valine, DL-leucine, serine, aspartic acid, histidine, and asparagine). Ternary complexes are formed by a stepwise mechanism. The relative stabilities of the ternary complexes are compared with those of the corresponding binary complexes in terms of Δlog K, log X, and % R.S values. The concentration distribution curves of the various binary and ternary species in a solution were evaluated as a function of pH.

Anticoagulant activity of heparin increased by interaction with terbium ions and complexation with ADP, arginine, glycine, and proline: comparative analysis

A comparative analysis of blood plasma coagulation with the participation of terbium ions (Tb 3+ ) and complexes of high-molecular-weight heparin with endogenous ligands (adenosine triphosphate, arginine, glycine, and proline) has been performed using published data on the computer simulations of chemical equilibria, results of biochemical experiments in vitro with blood plasma of laboratory rats, and the modern enzymatic theory of blood clotting. The participation of Tb 3+ was investigated by computer simulation of chemical equilibria based on pH-metric data for the calcium chloride—terbium nitrate—unfractionated heparin system in physiological solution and by biochemical experiments in vivo with intraperitoneal injections of terbium heparinate and terbium chloride into laboratory rats. It is established that terbium heparinate at a concentration equivalent to 50 IU heparin and terbium chloride in the concentration range 1.5 10 –5 – 1.5 10 –2 act as coagulants. The hypothetical mechanism of competitive complexation of Tb 3+ and Ca 2+ with blood clotting factors is not confirmed by the results of biochemical experiments that are consistent with the modern enzymatic theory of blood clotting and the blood plasma component composition. Heparin complexes with blood plasma ligands were constructed by computer simulation of chemical equilibria based on pH-metric data for heparin-L and MCl2—heparin L (M = Ca 2+ and Mg 2+ ; L = ATP, Arg, Gly, Pro) systems in physiological solution and by biochemical experiments in vitro and in vivo with blood plasma of laboratory rats. Complexes of heparin with ATP, Arg, Gly, and Pro are non-toxic, contain organic cations of ligands bound to heparin sulfonates, and do not disrupt the enzymatic blood coagulation process. These complexes regulate the blood coagulation process by decreasing the equilibrium concentration of Ca 2+ (through the formation of stable complexes) and produce a two- to three-fold increase in heparin activity.

Thermodynamic study of Cu2+ binding to the DAHK and GHK peptides by isothermal titration calorimetry (ITC) with the weaker competitor glycine

The peptides Asp-Ala-His-Lys (DAHK) and Gly-His-Lys (GHK) are naturally occurring Cu(II)-chelating motifs in human serum and cerebrospinal fluid. Here, the sensitive thermodynamic technique isothermal titration calorimetry was used to study the energetics of Cu(II) binding to DAHK and GHK peptides in the presence of the weaker ligand glycine as a competitor. DAHK and GHK bind Cu(II) predominantly in a 1:1 stoichiometry with conditional dissociation constants [i.e., at pH 7.4, in the absence of the competing chelators glycine and 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid buffer] of 2.6 ± 0.4 × 10(-14) M and 7.0 ± 1.0 × 10(-14) M, respectively. Furthermore, the apparent ΔH values were measured and the number of protons released upon Cu(II) binding was determined by performing experiments in different buffers. This allowed us to determine the conditional ΔG, ΔH, and ΔS, i.e., corrected for the contributions of the weaker ligand glycine and the buffer at pH 7.4. We found that the entropic and enthalpic contributions to the Cu(II) binding to GHK and DAHK are distinct, with a enthalpic contribution for GHK. The thermodynamic parameters obtained correspond well to those in the literature obtained by other techniques, suggesting that the use of the weaker ligand glycine as a competitor in isothermal titration calorimetry provides accurate data for Cu(II) binding to high-affinity peptides, which cannot be accurately determined without the use of a competitor ligand.

Poly[di-μ-glycinato-copper(II)]: a two-dimensional coordination polymer

The title coordination polymer, [Cu(C2H4NO2)2]n, is two-dimensional and consists of a distorted octa­hedral copper coordination polyhedron with two bidentate glycine ligands chelating the metal through the O and N atoms in a trans-square-planar configuration. The two axial coordination sites are occupied by carbonyl O atoms of neighbouring glycine mol­ecules. The Cu—O distances for the axial O atoms [2.648 (2) and 2.837 (2) Å] are considerably longer than both the Cu—O [1.9475 (17) and 1.9483 (18) Å] and Cu—N [1.988 (2) and 1.948 (2) Å] distances in the equatorial plane, which indicates a strong Jahn–Teller effect. In the crystal, the two-dimensional networks are arranged parallel to (001) and are linked via N—H⋯O hydrogen bonds, forming a three-dimensional arrangement.

Utilizing the Adaptive Polyoxometalate [As2W19O67(H2O)]14– To Support a Polynuclear Lanthanoid-Based Single-Molecule Magnet

Five members of a new family of polyoxometalate (POM)-ligated tetranuclear rare earth metal complexes have been synthesized and characterized. These compounds have the general formula (HDABCO)(8)H(5)Li(8)[Ln(4)As(5)W(40)O(144)(H(2)O)(10)(gly)(2)]·25H(2)O [Ln = Gd (1), Tb (2), Dy (3), Ho (4) and Y = (5), HDABCO = monoprotonated 1,4-diazabicyclooctane, gly = glycine] and were synthesized from the preformed POM precursor [As(2)W(19)O(67)(H(2)O)](14-). The structure is comprised of two {As(2)W(19)O(68)} building blocks linked by a unit containing four rare earth ions and two additional tungsten centers, with the two glycine ligands playing a key bridging role. Two crystallographically distinct rare earth ions are present in each complex, both of which possess axially compressed, approximate square antiprismatic coordination geometry. The variable-temperature magnetic susceptibility profiles for 2-4 are dominated by population/depopulation of the M(J) sublevels of the relevant ground terms, and fitting of the data has afforded the ligand field parameters in each case, from which the energies of the M(J) sublevels can be calculated. Alternating current magnetic susceptibility data have revealed the onset of slow magnetic relaxation for 3, with the energy barrier to magnetization reversal determined to be 3.9(1) K. As for other lanthanoid complexes that display slow magnetic relaxation, this energy barrier is due to the splitting of the M(J) sublevels of the Dy(3+) ions such that the ground sublevel has a relatively large |M(J)| value, thereby affording Ising-type magnetic anisotropy. This complex is thus the first POM-supported polynuclear lanthanoid-based SMM. Simulation of the W-band EPR spectrum of 1 has afforded the spin Hamiltonian parameters for this species, while the X-band EPR spectrum of 3 indicates the presence of a non-negligible fourth-order transverse component of the anisotropy, which is responsible for the small effective energy barrier observed for 3 and the absence of slow magnetic relaxation for 4.

A glycine ligand coordinated hybrid complex constructed from hexanuclear copper clusters and octamolybdates

Abstract Self-assembly of the sodium molybdate, copper chloride and glycine in aqueous solution results in a novel compound, {[NaCu6(Gly)8(H2O)2][Mo8O26(GlyH)2(Cu(Gly)H2O)]2}{NaCu6(Gly)8(H2O)2}{Mo8O26(GlyH)2}·16H2O (1). Compound 1 contains a new unit of {[NaCu6(Gly)8(H2O)2][Mo8O26Cu(Gly)2]2}, in which the [Mo8O26Cu(Gly)2] polyoxometalate units are connected by the [NaCu6(Gly)8(H2O)2] hexanuclear copper cluster. The magnetic measurement of 1 shows that ferromagnetic coupling exists between the magnetic centers of the hexanuclear copper cluster.

Synthesis and characterization of mixed ligand complexes of lomefloxacin drug and glycine with transition metals. Antibacterial, antifungal and cytotoxicity studies

Mixed ligand complexes derived from lomefloxacin (LFX, L 1) as primary ligand and glycine (L 2) as secondary ligand have been prepared and characterized by conventional techniques including elemental analyses, XRD, infrared, electronic spectra, molar conductivity and thermal analyses. The elemental analyses data display the formation of 1:1:1 [M:L 1:L 2] complexes. The diffused reflectance and magnetic moment measurements reveal the presence of the complexes in an octahedral geometry. The infrared spectral data show that the chelation behavior of the ligands toward transition metal ions is through carbonyl O, and carboxylate O of LFX whereas the amino acid coordinate through the carboxylate oxygen and the amino nitrogen. The electronic spectral results display the existence of π–π∗ (phenyl rings), n–π∗ (NH 2 and C N) and confirm the mentioned structure. The molar conductivity reveals an electrolytic nature of all chelates. The thermogravimetric analysis data of the complexes displays the existence of hydrated and coordinated water molecules. The effect of LFX, glycine and their complexes on the inhibition of bacteria or fungi growth were evaluated. The prepared complexes were found to exhibit enhanced activity on bacteria or fungi growth compared to LFX and glycine ligands. LFX, [Mn(LFX)(Gly)(H 2O) 2]·Cl, [Co(LFX)(Gly)(H 2O) 2]·Cl and [Zn(LFX)(Gly)(H 2O) 2]·Cl were found to be very active against breast cancer cells with IC50 values 14, 11.2, 13 and 16.8, respectively, while glycine and other complexes had been shown to be inactive at lower concentration than 100 μg/ml.

ChemInform Abstract: Novel Indole-2-carboxylates as Ligands for the Strychnine-Insensitive N-Methyl-D-aspartate-Linked Glycine Receptor.

A series of indole-2-carboxylates were prepared and evaluated for their ability to inhibit the binding at the strychnine-insensitive glycine receptor that is associated with the NMDA-PCP-glycine receptor complex. All of the compounds were selective for the glycine site relative to other sites on the receptor macrocomplex and several of the compounds in this series were found to have submicromolar affinity for this receptor. The lead compound, 2-carboxy-6-chloro-3-indoleacetic acid (Ki = 1.6 microM vs [3H]glycine), was also found to noncompetitively inhibit the binding of MK-801, a ligand for the phencyclidine site on the receptor macrocomplex. These latter data suggest that the compound functions as an antagonist at the strychnine-insensitive glycine receptor. The structural activity relationships within this series of indole-2-carboxylates is discussed and several key pharmacophores are identified for this series of glycine ligands. In general, the most potent compounds were the C-3 acetamides, with N-propyl-2-carboxy-6-chloro-3-indoleacetamide having the highest receptor affinity.

Glycine receptor expression in the forebrain of male AA/ANA rats

Ethanol is known to directly interact with the glycine receptor (GlyR). GlyRs are membrane proteins and are constituted as either α-homomers or α-β heteromers with a subunit stoichiometry of 2α3β. Previous studies by our group have suggested a role for GlyRs and its endogenous ligands glycine and taurine in the mesolimbic dopamine activating and reinforcing effects of ethanol. Here we use quantitative PCR (qPCR) to compare the relative GlyR expression in Alko Alcohol/Non-Alcohol (AA/ANA) rats. These animals have been selectively bred to create distinct populations regarding alcohol consumption and preference, presumably mainly due to genetic differences. The aim of this study was to examine the relative gene expression of GlyR subunits (α1–3 and β) in different brain areas and relate it to alcohol consumption. The hypothesis was that AA/ANA rats are differently disposed to ethanol consumption due to their GlyR set-ups and/or compositions. Results from the present study indicate that α2 is the most widely expressed α-subunit in the forebrain regions and that the α2β-heteromer seems to be the most common subunit composition in this part of the CNS. Despite displaying different drinking behaviours the anticipated differences in mRNA expression were few. However, correlations found between alcohol consumption and/or preference and GlyR expression support a role for GlyRs in alcohol consumption. Tentative differences between AA and ANA animals related to GlyR transmission could therefore lie in, for example, the regulation of the levels of the endogenous ligand(s) for the receptor or in mechanisms downstream to GlyR activation.