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PubMed1996

Comparison of the new atypical antipsychotics olanzapine and ICI 204,636 with clozapine on behavioural responses to the selective "D1-like" dopamine receptor agonist A 68930 and selective "D2-like" agonist RU 24213.

The effects of the putative atypical antipsychotics olanzapine and ICI 204,636 on behavioural responses to the selective "D2-like" dopamine receptor agonist RU 24213 and to the selective "D1-like" agonist A 68930 were compared with those of the prototype atypical antipsychotic clozapine, the selective D1-like antagonist SCH 23390 and the selective D2-like antagonist YM 09151-2. Olanzapine (0.4-2.0 mg/kg) and ICI 204,636 (4.0-36.0 mg/kg), like clozapine (4.0-36.0 mg/kg) and SCH 23390 (0.01-1.0 mg/kg), effected at best modest reduction in typical sniffing and locomotor responses and, with the exception of ICI 204,636, released episodes of atypical myoclonic jerking to RU 24213 (12.5 mg/kg); a high dose of olanzapine (10.0 mg/kg), like YM 09151-2 (0.005-0.5 mg/kg), blocked all responsivity to RU 24213. Conversely, olanzapine (0.4-2.0 mg/kg) and ICI 204,636 (4.0-36.0 mg/kg), like clozapine (4.0-12.0 mg/kg) and SCH 23390 (0.01-0.1 mg/kg), readily blocked typical grooming responses to A 68930 (0.5 mg/kg); YM 09151-2 failed to block grooming and exerted more variable effects. Olanzapine and, to a lesser extent, ICI 204,636 share with clozapine a preferential action to attenuate D1-mediated function; given their lack of selective affinity for D1-like receptors, this common effect may be exerted at an alternative level of synaptic function. The action of olanzapine and particularly ICI 204,636 to release additional episodes of atypical vacuous chewing to A 68930 indicates some deviation from a wholly clozapine-like profile, the clinical significance of which remains to be specified.

Animals↗

PubMed1995

Pharmacology of selective and non-selective metabotropic glutamate receptor agonists at L-AP4 receptors in retinal ON bipolar cells.

Retinal ON bipolar cells possess metabotropic glutamate receptors (mGluRs) which are sensitive to L-2-amino-4-phosphonobutyric acid (L-AP4). Recent studies suggest there are multiple subtypes of L-AP4 receptors. In order to provide a more complete description of the pharmacology of the retinal L-AP4 receptor, we examined the actions of a number of compounds which are active at L-AP4 receptors and other mGluRs. Four groups of compounds were studied: (1) AP4 analogues (e.g. L-AP5, L-SOP, cyclobutylene AP5, and N-Me-AP4), (2) non-selective mGluR agonists (ibotenate and quisqualate), (3) selective mGluR agonists (L-CCG-I), and (4) agonists proposed to be selective for specific mGluR subtypes (DCG-IV and t-ADA). Concentration-response curves were obtained using the b-wave of the electroretinogram (ERG) as an assay for L-AP4 receptor activation. Whole cell voltage clamp recordings from ON bipolar cells in the retinal slice preparation of the mudpuppy were used to determine whether the compounds acted as L-AP4 receptor agonists. All compounds were L-AP4 receptor agonists, except t-ADA which was ineffective. The results reveal pharmacological differences between L-AP4 receptors in mudpuppy ON bipolar cells and those in other systems, consistent with the proposal that there are multiple L-AP4 receptor subtypes. For example, retinal L-AP4 receptors are more potently activated by L-AP5 than L-SOP, whereas L-SOP has been shown to be more potent than L-AP5 in L-AP4 receptors in the lateral perforant path (LPP) of the rat hippocampus. L-SOP is also relatively more potent at the cloned L-AP4 receptors mGluR4, 6, and 7 than in mudpuppy ON bipolar cells in situ. The different potencies of these compounds in retina and LPP is ascribed to both steric and charge factors. The results with DCG-IV and t-ADA are consistent with the proposal that these are subtype-selective agonists, but DCG-IV is likely to be selective only at very low concentrations (< or = 1 microM).

Aminobutyrates↗

PubMed1981

Effects of selective and non-selective beta-adrenergic agents on insulin secretion in vivo.

The effects of various beta-adrenergic agents on insulin secretion were investigated in vivo in mice. The non-selective beta-stimulator isopropylnoradrenaline and the selective beta 2-stimulator terbutaline both stimulated insulin secretion markedly, with the same efficacy and in a dose-dependent manner. The peak levels of plasma insulin after these two beta-agonists were achieved at a later time point (5-6 min) than after stimulation with glucose or carbachol (1.5-2.5 min). At very high dose levels the beta 2-stimulator isopropylaminothiazoloxypropanol slightly increased plasma insulin concentrations. The non-selective beta-blocker propranolol and the beta 2-selective blocker ICI 188,551 inhibited terbutaline-induced insulin release markedly and at comparable low dose levels, whereas the selective beta 1-blocker metoprolol exerted this effect only at a high dose level. At higher dose levels these three blockers moderately depressed the insulin response to glucose suggesting a partial dependence on intact beta-adrenoceptors for the effect of glucose. The beta 2-blocker butoxamine and the beta 1-blocker pamatolol did not influence insulin secretion. In conclusion, beta-adrenoceptor stimulation enhanced insulin secretion in vivo, but the beta-adrenoceptors regulating insulin secretion do not fit well into the conventional subdivision of beta 1 and beta 2, though they apparently are mainly of the beta 2-type.

Adrenergic beta-Agonists↗

PubMed2005

Effects of chronic neuroleptic treatments on nutrient selection, body weight, and body composition in the male rat under dietary self-selection.

New antipsychotic drugs often increase weight and produce metabolic disturbances in treated patients. However, the mechanisms by which neuroleptics induce these undesirable side effects in humans are not known. Studies have shown that antipsychotics can increase body weight in female but not in male rats. However, no studies investigated changes in macronutrient selection during chronic treatments with antipsychotics in male rats, and no studies investigated precisely body composition after such treatments. In the present work, we studied in male rats the effects of long-term administration of two neuroleptics: haloperidol, a classical neuroleptic which has a moderate effect on weight gain in humans, and olanzapine, an atypical neuroleptic which has a more important effect on weight gain. Treatments (both 1 mg/kg) were given orally for 6 weeks, and the animals were allowed to self-select food among carbohydrates, lipids and proteins. Food selection was measured throughout the study, and body composition was measured by dissection and weighing of the main organs and tissues. Circulating leptin, insulin and glucose were also assayed at the end of the study on blood collected at the time of carcass analysis. The results show that none of the neuroleptic treatments modified caloric intake, food selection, body weight, and body composition. Olanzapine produced a statistically non-significant increase in subcutaneous fat tissue. It is concluded that a 6-week olanzapine or haloperidol treatment in male rats under dietary macronutrient selection does not significantly affect energy regulation.

Adipose Tissue↗

PubMed2005

Metalloform-selective inhibition: synthesis and structure-activity analysis of Mn(II)-form-selective inhibitors of Escherichia coli methionine aminopeptidase.

Methionine aminopeptidase (MetAP) is a promising target for development of novel antibacterial, antifungal and anticancer agents. However, its physiologically relevant metal ion remains to be defined, and its inhibitors need to inhibit the in vivo metalloform. Based on the Mn(II)-form-selective inhibitors discovered by high throughput screening as leads, a series of analogs of 5-phenylfuran-2-carboxylic acid was prepared and subsequently evaluated on Co(II)-, Mn(II)-, Ni(II)-, and Fe(II)-forms of Escherichia coli MetAP, in order to define the structural elements responsible for their inhibitory potency and metalloform selectivity. Various substitutions on the phenyl ring changed their potency on the Mn(II)-form but not their metalloform selectivity. We conclude that the preferential coordination of the carboxyl group to Mn(II) ions is the major determinant for their superb selectivity toward the Mn(II)-form. Changing the carboxylate to hydroxamate alters its ability to bind and discriminate different metal ions, and the hydroxamate derivative becomes non-selective among the metalloforms tested.

Aminopeptidases↗

PubMed2004

The binding selectivity of ADAR2's dsRBMs contributes to RNA-editing selectivity.

ADAR2 is an RNA editing enzyme that deaminates adenosines in certain duplex structures. Here, we describe the role of its RNA binding domain, consisting of two copies of a common dsRNA binding motif (dsRBM), in editing site selectivity. ADAR2's dsRBMs bind selectively on a duplex RNA that mimics the Q/R editing site in the glutamate receptor B-subunit pre-mRNA. This selectivity is different from that of PKR's dsRBM I, indicating that dsRBMs from different proteins possess intrinsic binding selectivity. Using directed hydroxyl radical cleavage data, molecular models were developed that predict important recognition surfaces on the RNA for identified dsRBM binding sites. Blocking these surfaces by benzyl modification of guanosine 2-amino groups impeded RNA-editing, demonstrating a correlation between deamination efficiency by ADAR2 and selective binding by its dsRBMs. In addition, the editing activity of a mutant of ADAR2 lacking dsRBM I on N(2)-benzylguanosine-modified RNA suggests the location of the dsRBM I binding site that leads to editing at the GluR-B Q/R site.

Adenosine Deaminase↗

PubMed2006

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties.

Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase- or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors that were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP- and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the losses of dynamic compression and shear moduli were delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

Aggrecans↗

PubMed2006

Selectivity of neuronal adaptation does not match response selectivity: a single-cell study of the FMRI adaptation paradigm.

fMRI-based adaptation paradigms (fMR-A) have been used to infer neuronal stimulus selectivities in humans. Inferring neuronal selectivities from fMR-A, however, requires an understanding of the relationship between the stimulus selectivity of neuronal adaptation and responses. We studied this relationship by recording single cells in macaque inferior temporal (IT) cortex, an area that shows fMRI adaptation. Repetition of identical object images reduced the responsiveness of single IT neurons. Presentation of an image to which the neuron was unresponsive did not alter the response to a subsequent image that activated the neuron. Successive presentation of two different images to which the neuron responded similarly produced adaptation, but less so than the repeated presentation of an image. The neuronal adaptation at the single-cell level showed a greater degree of stimulus selectivity than the responses. This complicates the interpretation of fMR-A paradigms when inferring neuronal selectivity.

Adaptation, Physiological↗

PubMed2007

Neuropeptide Y (NPY) Y2 receptor-selective agonist inhibits food intake and promotes fat metabolism in mice: combined anorectic effects of Y2 and Y4 receptor-selective agonists.

Peripheral administration of the endogenous Y(2) and Y(4) receptor selective agonists, PYY(3-36) and PP, have been shown to inhibit food intake and body weight gain in rodents, and to reduce appetite and caloric intake in humans. We have previously developed a long-acting, potent and highly selective Y(2) receptor selective agonist, N-alpha-Ac-[Nle(24,28), Trp(30), Nva(31), Psi(35-36)]PYY(22-36)-NH(2) (BT-48). BT-48 (ip) dose-dependently inhibited ad lib food intake and also decreased the respiratory quotient in mice during both the light and dark periods. The latter observation is indicative of enhanced fat metabolism. Moreover, BT-48 also inhibited food intake in fasted mice. Combined ip administration of BT-48 (50nmol/mouse) with a highly potent and selective Y(4) anorectic peptide, BVD-74D (50nmol/mouse), resulted in a powerful and long lasting inhibitory effect on food intake. As expected, this inhibitory effect on food intake was nearly double that exhibited by either peptide (50nmol/mouse) alone. In summary, BT-48, unlike PYY(3-36), exhibits little or no affinity to other "Y" receptors, and may therefore have a better clinical potential than PYY(3-36) for control of food intake. Moreover, it appears that treatment with a combination of Y(2) and Y(4) receptor selective agonists may constitute a more powerful approach to control food intake than treatment with either of these agonists alone.

Adipose Tissue↗

PubMed2004

Gastrointestinal and hepatic toxicity of selective and non-selective cyclooxygenase-2 inhibitors in pregnant and non-pregnant rats.

The aim of the study was to evaluate the toxicity of non-selective (tolmetin, ibuprofen and piroxicam) and selective (DFU) cyclooxygenase-2 inhibitors on pregnant and non-pregnant rats. The drugs were administered orally once (DFU, piroxicam) or three times (tolmetin, ibuprofen) a day from days 8 through 21 of gestation experiment in three doses. The initial dose was similar to the human antiinflammatory one and set as 8.5 mg/kg (tolmetin, ibuprofen), 0.3 mg/kg (piroxicam) and 0.2 mg/kg (DFU). The middle dose was increased 10 times and the highest one 100 times the initial dose. The highest dose for ibuprofen was set at 200mg/kg due to high mortality. On gestation/experimental day 21 animals were sacrificed, blood was collected and abdominal organs were taken for pathological examination. Activity of alanine and asparate aminotransferases and levels of total protein and urea were determined. Stomach, small and large intestines, and liver were grossly and histologically examined. Dose-dependent mortality, signs of gastrointestinal toxicity, and significant changes of biochemical parameters were found in groups exposed to non-selective COX inhibitors in both pregnant and non-pregnant rats. Mild regressive structural hepatic changes were observed. Significant decrease of protein level in non-pregnant rats treated with high DFU dose, and occasionally observed gastrointestinal changes were the only changes noted in groups exposed to the selective COX-2 inhibitor. Tolerability of non-selective COX inhibitors was lower in both pregnant and non-pregnant groups when compared with DFU. Insignificant mortality and histological changes were noted between pregnant and non-pregnant groups.

Animals↗

PubMed1993

Selective shunts in selected older cirrhotic patients with variceal hemorrhage.

Whereas portal systemic shunts pose significant problems in many patients, they have long been thought to have particular risks when undertaken in older cirrhotic patients, with devastating encephalopathy reportedly common in older patients undergoing nonselective shunt surgery. With advances in anesthesia management and perioperative monitoring and the advent of selective shunting, we postulated that both the operative and long-term outcomes might be improved. In this context, we reviewed our recent experience with selective shunts [distal splenorenal (DSRS) and small-diameter interposition portacaval grafts (IPCG)] in patients over the age of 60 years with variceal bleeding. Nineteen consecutive cirrhotic patients over 60 years of age undergoing elective or urgent selective shunt surgery for variceal hemorrhage since 1986 were identified. Sixteen patients underwent DSRS, and 3 underwent IPCG. The etiologies of the cirrhosis were multiple, with 12 of 19 classified as Child's B or C disease. There were no operative deaths, and all but one patient returned home following the surgery. No patient has had recurrent bleeding or required further surgery for portal hypertension-related problems. Three of 19 developed encephalopathy, and 4 of 19 died of liver failure within 1 year of surgery. Of the 14 patients still alive and well (mean postoperative survival: 44 months, range: 4 to 74 months), all remain free of encephalopathy and live independently. Based on this experience, it would appear that one can anticipate satisfactory short- and long-term outcomes after selective shunt surgery in selected patients with variceal bleeding over the age of 60 years. These patients with portal hypertension should not, therefore, be rejected for shunt surgery based on age alone.

Age Factors↗

PubMed1988

Expert system for the selection of high-performance liquid chromatographic methods in pharmaceutical analysis. Validation of the rules for the selection of the mobile phase.

The rules for the selection of the mobile phase and the validation performed on 44 pharmaceutical preparations, containing one to five active compounds, are described. These rules are incorporated into an expert system, called LABEL, for the selection of high-performance liquid chromatographic methods in pharmaceutical analysis. A single stationary phase type is used, namely a nitrile or cyanopropyl (CN) column, which can be used in both normal-phase (NP) and reversed-phase (RP) chromatography. Three mobile phase systems were evaluated on this column type: NP, RP with water and RP with buffer. LABEL selects one of these three systems on the basis of the rules incorporated for the mobile phase selection, checks if the addition of ion-suppressing agents to the eluting agent is necessary and finally gives the starting composition of the mobile phase in each of the three systems. For this selection the number of compounds in the sample, the acid-base properties and the hydrophobicity of the solutes are the more important factors. The validation of the rules on 44 pharmaceutical preparations resulted in an immediate success in 82% of all cases. In half of the remaining cases, the system proposed can be adapted with a minor change in conditions, so that it can also be used in practice.

Chromatography, High Pressure Liquid↗

PubMed2000

Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors.

Cholinergic neurons degenerate in Alzheimer's disease, resulting in cognitive impairments and memory deficits, and drug development efforts have focused on selective M1 muscarinic agonists. 5-(3-Ethyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine trifluoroacetic acid (CDD-0102) stimulates M1 muscarinic receptors in rat brain [Messer, W.S., Jr., Abuh, Y.F., Liu, Y., Periyasamy, S., Ngur, D.O., Edgar, M.A., El-Assadi, A.A., Sbeih, S., Dunbar, P.G., Roknich, S., Rho, T., Fang, Z., Ojo, B., Zhang, H., Huzl, J.J., III, Nagy, P.I., 1997a. J. Med. Chem. 40, 1230-1246.] and improves memory function in rats with lesions of the basal forebrain cholinergic system. Moreover, CDD-0102 exhibits oral bioavailability, few side effects and low toxicity, and thus represents a viable candidate for clinical studies. Despite the development of functionally selective agonists such as xanomeline and CDD-0102, there is room for improvements in ligand affinity and selectivity. The high degree of amino acid homology within transmembrane domains has hindered the development of truly selective agonists. Site-directed mutagenesis, biochemical and molecular modeling studies have identified key amino acid residues such as Thr192 and Asn382 in the binding of agonist to M1 receptors [Huang, X.P., Nagy, P.I., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1999. Br. J. Pharmacol. 126, 735-745.]. Recent work has implicated residues at the top of transmembrane domain VI in the binding of muscarinic agonists and activation of M1 receptors [Huang, X.P., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1998. J. Pharmacol. Exp. Ther. 286, 1129-1139.]. Thus, residues such as Ser388 represent molecular targets for the further development of agonists with improved M1 receptor affinity, selectivity and activity.

Alzheimer Disease↗

PubMed2004

Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation.

The major side effect with the use of first generation of non selective monoamine oxidase (MAO) inhibitors as neuropsychiatric drugs was what became known as the "cheese reaction". Namely, potentiation of sympathomimetic activity of ingested tyramine present in cheese and other food stuff, resulting from its ability to release noradrenaline, when prevented from metabolism by MAO. The identification of two forms of MAO, termed types A and B and their selective irreversible inhibitors resolved some of this problems. However irreversible MAO-A inhibitors continue to induce a cheese reaction, whereas MAO-B inhibitors at their selective dosage did not and led to introduction of L-deprenyl (selegiline) as an anti-Parkinson drug, since dopamine is equally well metabolized by both enzyme forms. The cheese reaction is a consequence of inhibition of MAO-A, the enzyme responsible for metabolism of noradrenaline and serotonin, located in peripheral adrenergic neurons. The consequence of these findings were the development of reversible MAO-A inhibitors (RIMA), moclobemide and brofaromin, as antidepressants and possible anti-Parkinson activity, with limited tyramine potentiation, since the amine can displace the inhibitor from its binding site on the enzyme. It has always been deemed a greater pharmacological advantage to inhibit both forms of the enzymes to get the full functional activities of the amine neurotransmitters, and without inducing a "cheese reaction". This was not possible until recently, with the development of the novel cholinesterase-brain selective MAO-AB inhibitor, TV3326 (N-propargyl-(3R)-aminoidnan-5-yl-ethyl methylcarbamate hemitartiate), a carbamate derivative of the irreversible MAO-B inhibitor anti-Parkinson drug, rasagiline. This drug is a brain selective MAO-A and B inhibitor, with little inhibition of liver and small intestine enzymes. Pharmacologically it has limited tyramine potentiation, very similar to moclobemide and being a MAO-AB inhibitor it has the antidepressant, anti-Parkinson and anti-Alzheimer activities in the respective models used to develop such drugs.

Animals↗

PubMed1994

Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity.

A detailed evaluation of the DNA alkylation selectivity of (+)-CC-1065, ent-(-)-CC-1065 and a series of aborted and extended analogs possessing the CPI alkylation subunit is detailed and the refinement of a model that accommodates the offset AT-rich adenine N3 alkylation selectivity of the enantiomeric agents is presented. The natural enantiomers bind in the minor groove in the 3'-->5' direction starting from the adenine N3 alkylation site across a 2 base (N-BOC-CPI; i.e. 5'-AA), 3.5 base (CPI-CDPI1/CPI-PDE-I1; i.e. 5'-AAA), 5 base (CC-1065/CPI-CDPI2; i.e. 5'-AAAAA) or 6.5 base (CPI-CDPI3; i.e. 5'-AAAAAA) AT-rich site. In contrast, the unnatural enantiomers bind in the reverse 5'-->3' direction in the minor groove and the binding site necessarily starts at the first 5' base preceding the adenine N3 alkylation site and extends across the alkylation site to the adjacent 3' bases covering an AT-rich site of 2 bases (N-BOC-CPI; e.g., 5'-AA), 5 bases (CC-1065/CPI-CDPI2; eg. 5'-AAAAA), or 6.5 bases (CPI-CDPI3; e.g. 5'-AAAAAA). Notably, the model accommodates the unusual observation that both enantiomers of N-BOC-CPI alkylate the same sites within duplex DNA (5'-AA > 5'-TA) and the required reversed binding orientation of the enantiomeric agents. The reversed binding orientation is required to permit access to the electrophilic cyclopropane and the resulting offset AT-rich alkylation selectivity is the natural consequence of the diastereomeric relationship of the adducts. Three dimensional models of the natural and unnatural enantiomer alkylations are presented which clearly illustrate the offset binding sites. A fundamentally simple model for the CC-1065 DNA alkylation reaction, that accommodates the behavior of both enantiomers, is provided in which the sequence selectivity is derived from the noncovalent binding selectivity of the agents preferentially in the narrower, sterically more accessible AT-rich minor groove, the inherent steric accessibility to the adenine N3 alkylation site that accompanies deep penetration of the agent into the minor groove within an AT-rich site, and the 2 base-pair (N-BOC-CPI), 3.5 base-pair (CPI-PDE-I1/CPI-CDPI1), 5 base-pair (CC-1065/CPI-CDPI2), or 6.5 base-pair (CPI-CDPI3) site size required to permit agent binding in the minor groove at the alkylation site.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗

PubMed1999

Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors.

BACKGROUND: The lymphocyte-specific kinase Lck is a member of the Src family of non-receptor tyrosine kinases. Lck catalyzes the initial phosphorylation of T-cell receptor components that is necessary for signal transduction and T-cell activation. On the basis of both biochemical and genetic studies, Lck is considered an attractive cell-specific target for the design of novel T-cell immunosuppressants. To date, the lack of detailed structural information on the mode of inhibitor binding to Lck has limited the discovery of novel Lck inhibitors. RESULTS: We report here the high-resolution crystal structures of an activated Lck kinase domain in complex with three structurally distinct ATP-competitive inhibitors: AMP-PNP (a non-selective, non-hydrolyzable ATP analog); staurosporine (a potent but non-selective protein kinase inhibitor); and PP2 (a potent Src family selective protein tyrosine kinase inhibitor). Comparison of these structures reveals subtle but important structural changes at the ATP-binding site. Furthermore, PP2 is found to access a deep, hydrophobic pocket near the ATP-binding cleft of the enzyme; this binding pocket is not occupied by either AMP-PNP or staurosporine. CONCLUSIONS: The potency of staurosporine against Lck derives in part from an induced movement of the glycine-rich loop of the enzyme upon binding of this ligand, which maximizes the van der Waals interactions present in the complex. In contrast, PP2 binds tightly and selectively to Lck and other Src family kinases by making additional contacts in a deep, hydrophobic pocket adjacent to the ATP-binding site; the amino acid composition of this pocket is unique to Src family kinases. The structures of these Lck complexes offer useful structural insights as they demonstrate that kinase selectivity can be achieved with small-molecule inhibitors that exploit subtle topological differences among protein kinases.

Adenosine Triphosphate↗

PubMed2003

Selective acylation of 2 methoxynaphthalene by large pore zeolites: catalyst selection through molecular modeling.

The selective acylation of 2-methoxynaphthalene (2-MON) is commercially very important to produce selectively 2-acyl-6-methoxynaphthalene (2,6-AMON), which is a precursor to Naproxen, an anti-inflammatory drug. Most of the laboratory investigations conducted with different solid acids show that the undesirable products are formed in large quantities. Thus, various molecular modeling techniques were used to investigate selectivity towards desired 2,6-AMON isomer over undesired 1,2-AMON, in four large-pore zeolites, namely, mordenite (MOR), zeolite L (LTL), zeolite beta (BEA) and ITQ-7 (ISV). The qualitative results were obtained by using simple molecular graphics (MG) and structural fitting approach. The quantitative results were obtained by incorporating the interaction of atoms of the molecules and those of the zeolite frameworks. From diffusion energy profile calculations the diffusion energy barriers for self-diffusion of 2-MON and the acylated isomers were obtained. From these energy barrier values the selectivity offered by zeolites towards desired product was determined and it was found to be in the order of ISV>BEA>MOR>LTL. Hybrid Quantum Mechanics-Molecular Mechanics (QM/MM) approach was used to study the effect of Brønsted acidity on the activity and selectivity offered by zeolites. The interaction of the reactant and product species with the acidic protons at T3 and T9 sites in BEA, having different acidities was studied by this method. The QM energy values indicate that acidity affected the catalytic activity but not the regioselectivity towards the desired 2,6-AMON isomer.

Journal Article↗

PubMed1994

Selectivity of polymer membrane-based ion-selective electrodes: self-consistent model describing the potentiometric response in mixed ion solutions of different charge.

Despite its well-documented limitations, the semiempirical Nicolsky-Eisenman equation is used throughout the existing analytical literature to describe the selectivity of modern polymer membrane-based ion-selective electrodes (ISEs). In this paper, a new quantitative description for the response/selectivity function based on ion-extraction equilibria at the sample/membrane interface is presented. The proposed selectivity formalism clearly illustrates the range of validity for the conventional Nicolsky-Eisenman formalism. Extended equations are derived describing the electrode response in an exact manner, particularly with respect to analyte and interfering ions of different charge. The expression obtained corresponds to the matched potential method proposed previously by Christian and co-workers on the basis of solely empirical observations. Selectivity coefficients required for a given analytical problem with a predefined maximum error can now be predicted more accurately. Such predictions with respect to analyte and interfering ions of varying charges differ by 1-2 orders of magnitude in comparison to the selectivity values required on the basis of the extended Nicolsky-Eisenman formalism.

Electrochemistry↗