CH3 Substitution Research Articles

Structure, Dynamics, and Reactivity of Encapsulated Molecules in Restricted Spaces: Arylazoisoxazoles within an Octa Acid Capsule.

In this study, a well-defined organic capsule assembled from two octa acid (OA) molecules acting as host and select arylazoisoxazoles (AAIO) acting as guests were employed to demonstrate that confined molecules have restricted freedom that translates into reaction selectivity in both ground and excited states. The behavior of these AAIO guests in confined capsules was found to be different from that found in both crystals, where there is very little freedom, and in isotropic solvents, where there is complete freedom. Through one-dimensional (1D) and two-dimensional (2D) 1H NMR spectroscopic experiments, we have established a relationship between structure, dynamics and reactivity of molecules confined in an OA capsule. Introduction of CF3 and CH3 substitution at the 4-position of the aryl group of AAIO reveals that in addition to space confinement, weak interactions between the guest and the OA capsule control the dynamics and reactivity of guest molecules. 1H NMR studies revealed that there is a temperature-dependence to guest molecules tumbling (180° rotation along the capsular short axis) within an OA capsule. While 1H NMR points to the occurrence of tumbling motion, MD simulations and simulation of the temperature-dependent NMR signals provide an insight into the mechanism of tumbling within OA capsules. Thermal and photochemical isomerization of AAIO were found to occur within an OA capsule just as in organic solvents. The observed selectivity noted during thermal and photo induced isomerization of OA encapsulated AAIOs can be qualitatively understood in terms of the well-known concepts due to Bell-Evans-Polanyi (BEP principle), Hammond and Zimmerman.

Structural characterization of Russula griseocarnosa polysaccharide and its improvement on hematopoietic function

The hematopoietic function of a polysaccharide derived from Russula griseocarnosa was demonstrated in K562 cells, and subsequently purified through chromatography to obtain RGP1. RGP1 is a galactan composed of 1,6-α-D-Galp as the main chain, with partial substitutions. A -CH3 substitution was detected at O-3 of 1,6-α-D-Galp. The possible branches at O-2 of 1,6-α-D-Galp was α-L-Fucp. In mice with cyclophosphamide (CTX)-induced hematopoietic dysfunction, RGP1 alleviated bone marrow damage and multinucleated giant cell infiltration of the spleen, increased the number of long-term hematopoietic stem cells, and regulated the levels of myeloid cells in the peripheral blood. Furthermore, RGP1 promoted the differentiation of activated T cells and CD4+ T cells without affecting natural killer cells and B cells. Proteomic analysis, detection of cytokines, and western blotting revealed that RGP1 could alleviate hematopoietic dysfunction by promoting the activation of CD4+ T cells and the Janus kinase/ signal transducer and activator of transcription 3 pathway. The present study provides experimental evidence to support the application of RGP1 in CTX-induced hematopoietic dysfunction.

π-Hole Triel Bonds between TrPhX2 (Tr = B, Al, Ga; X = F, Cl, Br, CH3, OH) and (BH)2(NHC)2 (NHC = Nitrogen-Heterocyclic Carbene)

The π-hole triel bond formed by (BH)2(NHC)2 (NHC denotes nitrogen-heterocyclic carbene) and TrPhX2 (Tr = B, Al, and Ga; X = F, Cl, Br, CH3, and OH) was investigated computationally, with the B=B bond in (BH)2(NHC)2 being the electron donor. A large interaction energy ensures that the complex is quite stable. When the substituent X in the electron acceptor is fixed, the magnitude of the interaction energy varies with the identity of the Tr atom. When Tr is Al or Ga, the interaction energy is stronger than when it is B. With an increase in the electron-withdrawing ability of the substituents, the interaction energy shows distinct changes. When Tr is B or Al, the interaction energy varies as TrPhBr2 > TrPhCl2 > TrPhF2, which is different from the order of their positive electrostatic potentials. When Tr = Ga, the interaction energy hardly changes with an increase in the electronegativity of the halogen atoms. For CH3 and OH substitution, larger interaction energies were obtained, with the interaction energy for the OH substituent being the largest. The main interactions in these systems are a triel bond and an X· ·H hydrogen bond. When the substituents are fixed, the interaction energy of the triel bond increases in the order AlPhX2 < GaPhX2 < BPhX2, which is different from the order of the positive electrostatic potentials on the Tr atom in TrPhX2. When X is a halogen atom, the interaction energy of the triel bond decreases in the order Br > Cl > F, which is opposite to the trend for the positive electrostatic potentials on Tr in TrPhX2. In most complexes, the interaction energy for the hydrogen bond is less than that for the triel bond; there is no hydrogen bond in the methyl-substituted complex. In general, the interaction energy of the hydrogen bonds increases with an increase in the electronegativity of the halogen atoms.

Unoccupied Electronic States and Potential Barrier in Films of Substituted Diphenylphthalides on the Surface of Highly Ordered Pyrolytic Graphite

The results of a study of the unoccupied electronic states of ultrathin films of bis-carboxyphenyl-phthalide (DCA-DPP) and bis-methylphenyl-phthalide (DM-DPP) up to 8 nm thick are presented. The studies are carried out by total current spectroscopy (TCS) in the energy range from 5 to 20 eV above EF during thermal vacuum deposition of these organic films on the surface of highly ordered pyrolytic graphite (HOPG). The values of Evac relative to EF, i.e., the work function of electrons of the DM-DPP films at a film thickness of 5–8 nm are found to be 4.3 ± 0.1 eV. The values of the work function of electrons of the DCA‑DPP films are found to be 3.7 ± 0.1 eV. The structure of the maxima of unoccupied electronic states of DCA-DPP and DM-DPP films in the studied energy range is established. A comparison of the obtained properties of DCA-DPP and DM-DPP films with the properties of films of molecules of unsubstituted diphenylphthalide (DPP) is presented. Thus, the –CH3 substitution of the DPP molecule has almost no effect on the height of the potential barrier between the film and the HOPG surface, while –COOH substitution of the DPP molecule leads to an increase in the height of the potential barrier between the film and the HOPG substrate surface by 0.5–0.6 eV. Substitution of DPP molecules with –COOH functional groups and, thus, the formation of DCA-DPP molecules lead to a shift of two maxima of the fine structure of the total current spectra located at energies in the range from 5 to 8 eV above EF by about 1 eV towards the lower electron energies.

Незаполненные электронные состояния и потенциальный барьер в пленках замещенных дифенилфталидов на поверхности высокоупорядоченного пиролитического графита

The results of a study of the unoccupied electronic states of ultrathin films of bis-carboxyphenyl-phthalide (DCA-DPP) and bis-methylphenyl-phthalide (DM-DPP) up to 8 nm thick are presented. The studies were carried out by total current spectroscopy (TCS) technique in the energy range from 5 eV to 20 eV above EF during thermal vacuum deposition of these organic films on the surface of highly oriented pyrolytic graphite (HOPG). The energy Evac relative to EF, that is, the electronic work function of the DM-DPP films, at a film thickness of 5–8 nm was 4.3 ± 0.1 eV. The electronic work function of the DCA-DPP films was 3.7 ± 0.1 eV. The structure of the maxima of the unoccupied electronic states of DCA-DPP films and DM-DPP films in the studied energy range is determined. The properties determined of DCA-DPP and DM-DPP films are compared with the properties of films of unsubstituted diphenylphthalide (DPP). According to our analysis, –CH3 substitution of the DPP molecule practically did not affect the height of the potential barrier between the film and the HOPG surface, and –COOH substitution of the DPP molecule led to an increase in the height of the potential barrier between the film and the HOPG substrate surface by 0.5–0.6 eV. Substitution of DPP molecules with –COOH functional groups which represents formation of DCA-DPP molecules led to a shift of two peaks of the experimental total current spectra located at energies in the range from 5 eV to 8 eV above EF, by about 1 eV towards lower electron energies.

Chiral Self Recognition: Interactions in Propylene Oxide Complexes.

We elucidate the subtle energetic effects that give rise to chiral recognition in the propylene oxide dimer. Specifically, we investigate six homochiral (RRx) and six heterochiral (RSx) structures of this complex, with the RRn-RSn pair sharing the same pattern of weak O···H-C hydrogen bonds but subtly differing in energy due to chiral effects. The interaction energies for the 12 structures are computed at various levels of electronic structure theory and basis set up to the complete basis set limit of the coupled-cluster approach with single, double, and perturbative triple excitations (CCSD(T)). These benchmark interaction energies are compared to the results of various approximate approaches, both density functional theory-based and wave function-based. We find that while the RRn-RSn diastereomeric energy differences exhibit a great deal of error cancellation between the individual interaction energies, most approximate methods have a hard time even reproducing the correct signs of these differences consistently. The origins of the RRn-RSn differences are elucidated by several symmetry-adapted perturbation theory (SAPT) analyses ranging from ordinary intermolecular SAPT to a functional-group SAPT (F-SAPT) decomposition of direct and indirect H → CH3 substitution effects leading from achiral ethylene oxide complexes to chiral propylene oxide ones. It is shown that the largest diastereomeric energy differences are correlated to the variations in the electrostatic and dispersion SAPT contributions. Finally, the effect of chiral interactions on the vibrational frequencies of a propylene oxide molecule is investigated, showing that the interaction results in largest frequency shifts, splittings, and chiral discrimination effects in the lowest, torsional vibrational mode of the noninteracting monomer.

Photoluminescence of europium and terbium trifluoroacetylacetonates. Participation of LMCT state in processes of the energy transfer to Eu3+ ion

The effect of fluorination on spectroscopic properties of europium and terbium trifluoroacetylacetonates Ln(TFAA)3·2H2O, Ln(TFAA)3·Phen and Ln(TFAA)3·Bpy in the solid state have been investigated. A threefold increase in the luminescence intensity of europium compounds at -CF3 for −CH3 substitution in the β-diketonate ligand was obtained at 77 and 295 K. Different mechanisms of the excitation energy transfer to Ln3+ ions in europium and terbium compounds, which result in a drop in the luminescence efficiency at elevated temperatures, have been analyzed. A key role of ligand-metal charge transfer (LMCT) states in the processes of sensitization of the europium trifluoroacetylacetonates is demonstrated. Expansion of the energy gap between the LMCT state and the lowest triplet state T1 at fluorination gives rise to an increase in the excitation efficiency of the Eu3+ luminescence at 295 K. The back-transfer energy 5D4-T1 in the terbium trifluoroacetylacetonates is the main reason for shortening the 5D4 lifetime and decreasing the luminescence efficiency. The energy dissipation processes in the lanthanide TFAA adducts with heterocyclic diimines are mainly related to the β-diketonate ligand.

Theoretical Probing of Weak Anion-Cation Interactions in Certain Pyridinium-Based Ionic Liquid Ion Pairs and the Application of Molecular Electrostatic Potential in Their Ionic Crystal Density Determination: A Comparative Study Using Density Functional Approach.

A comprehensive study on the structure, nature of interaction, and properties of six ionic pairs of 1-butylpyridinium and 1-butyl-4-methylpyridinium cations in combination with tetrafluoroborate (BF4-), chloride (Cl-), and bromide (Br-) anions have been carried out using density functional theory (DFT). The anion-cation interaction energy (ΔEint), thermochemistry values, theoretical band gap, molecular orbital energy order, DFT-based chemical activity descriptors [chemical potential (μ), chemical hardness (η), and electrophilicity index (ω)], and distribution of density of states (DOS) of these ion pairs were investigated. The ascendancy of the -CH3 substituent at the fourth position of the 1-butylpyridinium cation ring on the values of ΔEint, theoretical band gap and chemical activity descriptors was evaluated. The ΔEint values were negative for all six ion pairs and were highest for Cl- containing ion pairs. The theoretical band gap value after -CH3 substitution increased from 3.78 to 3.96 eV (for Cl-) and from 2.74 to 2.88 eV (for Br-) and decreased from 4.9 to 4.89 eV (for BF4-). Ion pairs of BF4- were more susceptible to charge transfer processes as inferred from their significantly high η values and comparatively small difference in ω value after -CH3 substitution. The change in η and μ values due to the -CH3 substituent is negligibly small in all cases except for the ion pairs of Cl-. Critical-point (CP) analyses were carried out to investigate the AIM topological parameters at the interionic bond critical points (BCPs). The RDG isosurface analysis indicated that the anion-cation interaction was dominated by strong Hcat···Xani and Ccat···Xani interactions in ion pairs of Cl- and Br- whereas a weak van der Waal's effect dominated in ion pairs of BF4-. The molecular electrostatic potential (MESP)-based parameter ΔΔVmin measuring the anion-cation interaction strength showed a good linear correlation with ΔEint for all 1-butylpyridinium ion pairs (R2 = 0.9918). The ionic crystal density values calculated by using DFT-based MESP showed only slight variations from experimentally reported values.

Synthesis, characterization and biological screening of pyrazole-conjugated benzothiazole analogs.

Benzothiazole and pyrazoles are two important pharmacophores, the activity can be enhanced by conjugating them. Here, two novel series of the pyrazole-conjugated benzothiazole derivatives were synthesized. Synthesized compounds were characterized by Fourier-transform infrared, LC-MS, 1H NMR and 13C NMR spectroscopic techniques. Synthesized compounds exhibited moderate antimicrobial, antioxidant and excellent anti-TB activities. In in vitro anti-TB activity, 4d and 4e exhibited 1.6μg/ml minimum inhibitory concentration value. In order to rationalize the anti-TB activity, molecular docking studies were carried out and they were correlated with the in vitro results. Compounds containing electron donating groups show the promising antimicrobial and antioxidant activities, compounds with CH3 and Cl substitution show excellent anti-TB activity. Synthesized molecules may become potential candidates for the clinical trials.

Poly Ionic Liquid Solid Electrolyte Interphase (SEI) Formation in an Improvement of 5V Class Lithium Ion Batteries

Electric vehicles (EVs) are poised to dominate the next generation of transportation, but meeting the power requirements of EVs with lithium ion batteries is challenging because electrolytes containing LiPF6 and carbonates do not perform well at high temperatures and voltages. However, lithium benzimidazole salt is a promising electrolyte additive that can stabilize LiPF6 through a Lewis acid–base reaction [1]. The imidazole ring is not eligible for high-voltage applications owing to its resonance structure, but in this research, electron-withdrawing (−CF3) and electron-donating (−CH3) substitutions on imidazole rings were investigated. According to the calculation results, the CF3 substitution facilitates a high electron cloud density on imidazole ring structures to resist the electron releases from bezimidazole in oxidation reactions. In addition, through CF3 substitution, electrons are accepted from the lattice oxygen (O2−) in Lithium-rich (Li-Excess) layer material and O− is converted by electron to a great quantity, which catalyzes the electrolyte reduction and forms a new polyionic liquid solid electrolyte interphase on the cathode’s surface. Furthermore, the cycle performance tested at 60 °C and 4.8 V showed that the CF3 substitution maintains the battery retention effectively and exhibits almost no fading compared with both the blank electrolyte and the CH3 substitution. In addition, the results of this study confirm that bezimidazole salt greatly catalyzed the reduction of EC to a stage II reaction, and therefore less Li2CO3 formation was found. A possible reaction mechanism is shown in Figure 1. Figure 1

Neuroprotective and antioxidant effects of novel benzofuran-2-carboxamide derivatives.

In the present study, we synthesized a series of novel 7-methoxy-N-(substituted phenyl)benzofuran-2-carboxamide derivatives in moderate to good yields and evaluated their neuroprotective and antioxidant activities using primary cultured rat cortical neuronal cells and in vitro cell-free bioassays. Based on our primary screening data with eighteen synthesized derivatives, nine compounds (1a, 1c, 1f, 1i, 1j, 1l, 1p, 1q and 1r) exhibiting considerable protection against the NMDA-induced excitotoxic neuronal cell damage at the concentration of 100 μM were selected for further evaluation. Among the selected derivatives, compound 1f (with -CH3 substitution at R2 position) exhibited the most potent and efficacious neuroprotective action against the NMDA-induced excitotoxicity. Its neuroprotective effect was almost comparable to that of memantine, a well-known NMDA antagonist, at 30 μM concentration. In addition to 1f, compound 1j (with -OH substitution at R3 position) also showed marked anti-excitotoxic effects at both 100 and 300 μM concentrations. These findings suggest that -CH3 substitution at R2 position and, to a lesser degree, -OH substitution at R3 position may be important for exhibiting neuroprotective action against excitotoxic damage. Compound 1j was also found to scavenge 1,1-diphenyl-2-picrylhydrazyl radicals and inhibit in vitro lipid peroxidation in rat brain homogenate in moderate and appreciable degrees. Taken together, our structure-activity relationship studies suggest that the compound with -CH3 substitution at R2 and -OH substitution at R3 positions of the benzofuran moiety might serve as the lead exhibiting potent anti-excitotoxic, ROS scavenging, and antioxidant activities. Further synthesis and evaluation will be necessary to confirm this possibility.

Structure and vibrational assignment of bis(benzoylacetonato)copper(II)

Fourier transform Raman (3200–150cm−1) and infrared (4000–100cm−1) spectral measurements have been made for the solid copper (II) benzoylacetonate, Cu(bzac)2 and, for comparison, copper (II) acetylacetonate, Cu(acac)2. The molecular electronic energies, equilibrium geometries, IR and Raman spectra, and the internal coordinates for the vibrational modes have been computed for the cis and trans structures of Cu(bzac)2 at the B3LYP/6-311G* level of theory. Potential energy distribution (PED) and normal mode analysis have also been performed. A complete assignment of the observed band frequencies has been proposed. Comparing of observed and calculated vibrational spectra suggests that the predominant isomer in the sample is the trans isomer.To realize the effect of CH3 substitution by phenyl group on the structure, metal–O bond strength, and vibrational spectra, the geometrical parameters and vibrational wavenumbers of Cu(acac)2 were also calculated at the same level of theory. The calculated vibrational frequencies were compared with the experimental results. All of the measured IR and Raman bands were interpreted in terms of the calculated vibrational modes. The metal–O bond strength was investigated by geometry calculations and spectroscopic results. All theoretical and vibrational spectroscopic studies confirm stronger metal–ligand bond in Cu(bzac)2 than that in Cu(acac)2.

The Standard Enthalpies of Formation of Energetic 4,5-dinitroimidazole derivatives: A Theoretical Study

The standard enthalpies of formation for 7 derivatives of 4,5-dinitroimidazole in gas at 298 K were determined using isodesmic reactions at B3LYP/6-311G** and B3P86/6-311G** levels. The results indicate that the substitution of nitro group can increase the enthalpies of formation. The more the number of nitro group, the higher the enthalpies of formation. The standard enthalpies of formation of –NO2 and –CH3 substitution compounds on N atom are larger than corresponding ones on C atom.

Vibrational spectroscopic and DFT calculation studies of cobalt(II) complexes with 3-hydroxypicolinic acid

Two cobalt(II) complexes with 3-hydroxypicolinic acid (3-hydroxypyridine-2-carboxylic acid, 3-OHpicH), trans-[Co(3-OHpic)2(py)2] (2) and cis-[Co(3-OHpic)2(4-pic)2] (3) (py=pyridine; 4-pic=4-picoline or 4-methylpyridine), previously synthesized and characterized by X-ray diffraction, are here studied by Raman and mid-infrared spectroscopy with the help from the corresponding DFT vibrational calculations using B3LYP/6-311G(d,p) computational model. Intramolecular O–H⋯O hydrogen bond appears in both complexes 2 and 3, while weak C–H⋯O hydrogen bonds assemble molecules of 2 or 3 into 3D architecture. A complete presentation of all Raman, infrared and theoretical results is given for complex 3. The measured spectra are shown, relative intensities and bandwidths are discussed and the assignment of vibrational bands is given on the basis of the DFT calculations. The calculated spectra agree very well with the presented experimental findings, thanks to the suitable grouping of modes. The same vibrational calculations also reveal insignificant influence of H→CH3 substitution for the spectroscopic characterization of the complex. A careful study of differences between calculated and observed wavenumbers suggests that modified single-factor scaling is actually better than the classic multi-factor scaling approach.

End-substitution effect on the geometry and electronic structure of oligoheterocyclics

The end-substitution effects on the geometric and electronic structures of oligoheterocyclics are systematically studied using the density functional theory. It is found that the influence of the end-substitution does not depend on the heteroatom. End-substitution plays a fine-tune effect on the geometry and the excitation state. While the influences on the conducting type (p-type or n-type) and the inter-chain charge carrier hoping channels are much different between the electron-donating –CH3 and electron–accepting –CN substitutions. Both molecular electrostatic potentials and charge carrier injection rates indicate that the –CH3/–CH3 substitution is beneficial to the p-type doping, while the –CN/–CN substitution is in favor of the n-type doping, which is in agreement with the experimental observations. The –CH3 substituted packing dimers exert similar intermolecular interactions to the unsubstituted ones. The –CN substituted packing dimers yield much stronger intermolecular interactions comparing to the –CH3 substituted ones. It could be anticipated that the –CN substitution would be helpful to the charge carrier hopings between chains and thereby enhance the conductivity.

A Cl? anion-responsive luminescent Eu3+ complex with a chiral tripod: ligand substituent effects on ternary complex stoichiometry and anion sensing selectivity

A new series of N3,O-mixed donor tripods was prepared for luminescent Eu3+ complexes, in which the soft quinoline nitrogen, tertiary amine nitrogen, and hard amide oxygen donors were cooperatively involved. The mixed donor tripods formed more stable 1 : 1 complexes with Eu(NO3)3, La(NO3)3 and Tb(NO3)3 than the corresponding N4 donor tripods, and their Eu3+ complexes particularly exhibited anion-responsive luminescence properties. NMR, UV, and luminescence spectroscopic characterizations revealed that -CH3 substitution on the tripod skeleton remarkably altered the preferred stoichiometry of the "tripod-Eu3+-anion" ternary complex and gave anion-dependent europium luminescence. Although the disubstituted tripod preferred to form non-luminescent 2 : 1 (tripod : Eu3+) complexes with Eu(NO3)3 and other salts, it formed a luminescent 1 : 1 complex with EuCl3. Thus, this type of tripod offered Cl- anion-selective luminescence enhancement that was easily observed by the naked eye.

PMR studies of molecular motions, phase transitions and quantum tunnelling in NH4SnCl3 and N(CH3)4SnCl3

Molecular reorientation and low temperature relaxation effects of NH+ 4 ion and the effect of CH3 substitution (in place of H) are investigated by proton spin lattice relaxation time (T1) measurements at 10 MHz in NH4SnCl3 and N(CH3)4SnCl3 in the temperature range 4.2 K upto the melting points of the compounds (≊ 440 K). Phase transitions around 360 K in NH4SnCl3 and around 361 and 116K in N(CH3)4SnCl3 have been observed. In NH4SnCl3, the high temperature minimum at 330.5 K is attributed to the translational diffusion of the NH+ 4 ions, while the other T1, minima at 103.5, 60 and 50 K are ascribed to the reorientations of the NH+ 4 ion about the C2 and C3 axes. The low temperature minimum at 13.5 K is attributed to rotational tunnelling of the NH+ 4 ions. In N(CH3)4SnCl3, in addition to the high temperature minima at 212.2 and 182.6 K due to N(CH3)4 tumbling and CH3 reorientation, a temperature independent T1 behaviour between 83 and 31 K is observed, below which T1 decreases and tends to go through a minimum around 5 K. This low temperature minimum is attributed to rotational tunnelling of the CH3 groups. The motional parameters and tunnel frequencies are estimated.

The effect of N-methylation on helical peptides.

In N-methyl amino acids, the hydrogen of the N-H group is replaced with a bulky methyl group. While this change is expected to destabilize helical structures, the amount of destabilization is not known. Here the N-methyl group is placed into several positions of the helical peptides, acetyl-WGG(EAAAR)4A-amide and acetyl-WGG(RAAAA)4R-amide, and the melting of the peptides followed using CD. When analyzed using a simple two-state model, the destabilization associated with the H to CH3 substitution at 0 degree C is between 0.3 to 1.7 kcal/mole and is position dependent. The melting data may also be analyzed using a modified form of the Lifson-Roig statistics that should more correctly model the helix-coil transition in this small peptide. This analysis fails, however, apparently because the destabilization energy is greater than the energy that can be attributed to a single residue in this model.

The effect of N‐methylation on helical peptides

In N-methyl amino acids, the hydrogen of the N-H group is replaced with a bulky methyl group. While this change is expected to destabilize helical structures, the amount of destabilization is not known. Here the N-methyl group is placed into several positions of the helical peptides, acetyl-WGG(EAAAR)4A-amide and acetyl-WGG(RAAAA)4R-amide, and the melting of the peptides followed using CD. When analyzed using a simple two-state model, the destabilization associated with the H to CH3 substitution at 0°C is between 0.3 to 1.7 kcal/mole and is position dependent. The melting data may also be analyzed using a modified form of the Lifson-Roig statistics that should more correctly model the helix-coil transition in this small peptide. This analysis fails, however, apparently because the destabilization energy is greater than the energy that can be attributed to a single residue in this model. © 1997 John Wiley & Sons, Inc. Biopoly 40: 609–616, 1996

The in vitro effects of benzodiazepines on the rat diaphragm. Structure-activity relationships.

The effect of three different subgroups of benzodiazepines on the indirectly evoked twitch tension was investigated in the in vitro rat phrenic nerve - hemidiaphragm preparation. Two effects were observed: an initial increase in twitch tension at lower concentrations with some benzodiazepines, and a concentration-dependent depression at higher concentrations with all benzodiazepines. Significant differences for these effects were observed among the three subgroups of benzodiazepines and additionally within the subgroup of the 1,4-benzodiazepine-2-ketones. Structural requirements for both effects were different. For the increase of twitch tension a --CH3 substitution at R1 and a --F substitution at R2' were beneficial. For the twitch depression an --OH substitution at R3 and a --C1 substitution at R2' were optimal. An interaction between substituents at different substitution sites occurred. The potency of twitch depression showed a good correlation with literature reports of pKa values and a poor-to-inverse correlation with lipophilicity indices. A benzodiazepines antagonist, Ro 15-1788, caused no change in twitch tension in the concentration range of the investigated benzodiazepines nor did it prevent the twitch depression caused by benzodiazepines.