Pharmacological characterization of the allosteric modulator desfor...
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2010 Sep 1;334(3):917-26. doi: 10.1124/jpet.110.167684. Epub
2010 Jun 1.Pharmacological characterization of the allosteric modulator desformylflustrabromine and its interaction with alpha4beta2 neuronal nicotinic acetylcholine receptor orthosteric ligands.1, .1Department of Chemistry and Biochemistry, University of Alaska, 900 Yukon Drive, Fairbanks, AK 99775, USA.AbstractNeuronal nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of ligand-gated ion channels. nAChRs are involved in modulating nicotinic-based signal transmission in the central nervous system and are implicated in a range of disorders. Desformylflustrabromine (dFBr) is a positive allosteric modulator that potentiates alpha4beta2 nAChRs. It has been reported that dFBr is selective for the alpha4beta2 receptor relative to other common nAChR subtypes (Neurosci Lett 373:144-149, 2005). Coapplication of dFBr with acetylcholine (ACh) produces a bell-shaped dose-response curve with a peak potentiation of more than 265% (Bioorg Med Chem Lett 17:, 2007) at dFBr concentrations &10 microM and inhibition of responses at concentrations &10 microM. The potentiation and inhibition components of dFBr-modulated responses were examined by using two-electrode voltage clamp and human alpha4beta2 nAChRs expressed in Xenopus laevis oocytes. Currents to both partial and full agonists were potentiated by dFBr. Responses to low-efficacy agonists were potentiated significantly more than responses to high-efficacy agonists. Antagonist pIC(50) values were unaffected by coapplication of dFBr. In addition to its potentiating effects, dFBr was able to induce current spikes when applied to desensitized receptors, suggestive of a shift in equilibrium from the desensitized to open conformation. In contrast to potentiation, inhibition of ACh responses by dFBr depends on membrane potential and is probably the result of open-channel block by dFBr and ACh. Our data indicate distinct mechanisms for the potentiation and inhibition components of dFBr action. dFBr could prove useful for therapeutic enhancement of responses at alpha4beta2-containing synapses.PMID:
[PubMed - indexed for MEDLINE] PMCID: PMC2939658 Voltage dependence of potentiation and inhibition by dFBr. Membrane potential was increased in 10-mV steps from -100 to +20 mV using a two-electrode voltage clamp on α4β2 nAChR-expressing oocytes. Responses were obtained as discussed under Materials and Methods and normalized to those elicited by application of 1 mM ACh at -60 mV from the same oocyte. At least two batches of oocytes from different frogs were harvested for the experiments. Each data point represents at least n ≥4 replicates with error bars shown as ± S.E.M. For the control group (100 μM cytisine) the relationship between the induced response and the applied membrane potential is linear over the entire range of membrane potentials. Potentiating concentrations of dFBr (10 μM) coapplied with 100 μM cytisine show a similar linear relationship. Coapplication of 30 μM dFBr (inhibitory concentration) with 100 μM cytisine shows a nonlinear relationship between membrane potential and the induced response.J Pharmacol Exp Ther. ):917-926.dFBr-modulated responses to nAChR agonists and partial agonists. Responses were obtained from Xenopus oocytes under voltage-clamp conditions (Vm = -60 mV). Left, responses to agonists alone. Right, traces obtained at increasing concentrations of dFBr coapplied with fixed concentrations of either acetylcholine (A), nicotine (B), choline (C), or cytisine (D). Shown are the concentrations of agonist applied alone (left) or the concentration of dFBr and coapplied (right). The solid bar above the response traces indicates the time the oocyte was exposed to the agonist and/or dFBr. All traces for each set of responses were recorded from a single oocyte expressing α4β2 receptors (mRNA injected at a ratio of 1α/1β). Similar data obtained at varied agonist concentrations were pooled, and the data were plotted to produce the dose–response curves shown in Fig. 3 and the data shown in Table 1.J Pharmacol Exp Ther. ):917-926.Dose–response curves for agonists and partial agonists in the presence and absence of 1 μM dFBr. A, ACh. B, nicotine. C, choline. D, cytisine. dFBr and the appropriate concentration of agonist or partial agonist were coapplied to Xenopus oocytes expressing α4β2 receptors (mRNA injected at a ratio of 1α/1β). The peak current was measured, and responses were normalized to currents elicited by 1 mM ACh applied alone to the same oocyte. Each data point represents the combined data from at least four different experiments from a minimum of two different oocytes harvested from different frogs. Error bars indicate ± S.E.M. pEC50, Imax, and Hill slope (nH) were calculated by using nonlinear curve fitting algorithms and are shown in Table 1.J Pharmacol Exp Ther. ):917-926.Coapplication of dFBr with nAChR antagonists. Xenopus oocytes expressing α4β2 receptors (mRNA injected at a ratio of 1α/1β) were exposed to 1 mM ACh, and responses were inhibited by coapplication of increasing concentrations of DHβE (A), DMAB-anabaseine (B), or troposetron (C). Because individual peak amplitudes were normalized to those elicited by 1 mM ACh applied alone on the same oocyte, Imax values express peak currents relative to those obtained with 1 mM ACh. pIC50 values (bottom right) were determined by using nonlinear curve fitting as described under Materials and Methods. Data points represent at least four replicate values obtained from a minimum of two oocytes harvested from different frogs. Error bars indicate ± S.E.M.J Pharmacol Exp Ther. ):917-926.dFBr reactivates desensitized receptors. Acetylcholine or cytisine were bath-applied to Xenopus oocytes expressing α4β2 receptors at a rate of 3 ml/min for 30 s. During the desensitized portion of the response, 3-s pulses of either acetylcholine (A, top) or dFBr (A, bottom, B, and C) were repeatedly applied at a perfusion rate of 20 ml/min in the continued presence of agonist. Solid bars above the traces show the application of ACh or cytisine (continuous bar) and the repeated pulsed application of 1 μM dFBr (short lines on A, bottom, B, and C plots). A top, control trace showing repeated pulses of 10 mM acetylcholine applied during the desensitization period of a response to bath-applied 10 mM ACh. Minimal current was observed under these conditions. A bottom, application of 3-s pulses of 1 μM dFBr during the desensitization period produces large currents that decline back to baseline with repeated pulses of dFBr. B, application of 3-s pulses of 1 μM dFBr during the desensitization period of responses to 1 mM ACh produces similar effects to A bottom except pulses are broadened and show possible hump currents. C, application of 3-s pulses of 1 μM dFBr during the desensitization period of responses to 100 μM cytisine. Large currents were observed similar to those shown in A bottom but with a slower rate of decline. Each experiment was repeated at least four times on different oocytes harvested from at least two different frogs. The slope of the rising phase of the first peak generated by application of dFBr during the desensitizing period in each case was determined (activation slope): A bottom, -1020 ± 130 nA/s; B, -190 ± 9 nA/s; C, -66 ± 26 nA/s.J Pharmacol Exp Ther. ):917-926.The amplitudes of dFBr-induced currents on desensitized receptors decline during long exposures to dFBr. Responses were elicited by bath application of 1 mM ACh on Xenopus oocytes expressing α4β2 receptors. The top solid line above each trace indicates the time period during which the oocyte was exposed to ACh. The bottom line above the trace indicates the period of application of either ACh (B) or dFBr (A, C, and D). A, coapplication of 1 mM ACh and 1 μM dFBr for 48 s at a flow rate of 8 ml/min (no pre-exposure to ACh). B, control trace resulting from exposure to 1 mM ACh at a rate of 4 ml/min with 1 mM ACh applied during the desensitization period for 48 s at 8 ml/min. C, application of 1 μM dFBr at the peak of a response elicited by exposure to 1 mM ACh. ACh was present before, during, and after application of dFBr. D, application of 1 μM dFBr at the peak of a response elicited by exposure to 1 mM ACh. Unlike the experiment shown in C, perfusion of 1 mM ACh was discontinued during the application of 1 mM dFBr then restored at the end of the 48-s dFBr exposure. The responses shown were obtained from different oocytes. Because of different levels of receptor expression, no comparison of peak amplitudes was possible under these conditions.J Pharmacol Exp Ther. ):917-926.Publication TypesMeSH TermsSubstancesGrant SupportFull Text SourcesOther Literature SourcesMolecular Biology Databases
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):313-20. doi: 10.1124/jpet.111.182139. Epub
2011 Jul 26.AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase.1, , , , , , , , , , , .1AstraZeneca AB, Lund, Sweden.AbstractN-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1β. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.PMID:
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):53-62. doi: 10.1124/jpet.110.167007. Epub
2010 Apr 6.Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models.1, , , , , , .1Boehringer Ingelheim Pharma GmbH & Co. Biberach, Germany.Erratum inAbstractThe preclinical pharmacological profile of 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one monohydrochloride (olodaterol, previously known as BI 1744 CL), a novel, enantiomeric pure, inhaled human beta(2)-adrenoceptor (hbeta(2)-AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively). Likewise, olodaterol was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, antagonistic effects of single doses of olodaterol and formoterol were measured against acetylcholine challenges in anesthetized guinea pigs and dogs for up to 24 h by using the Respimat Soft Mist inhaler. Heart rate and metabolic parameters (serum potassium, lactate, and glucose) were monitored to evaluate systemic pharmacodynamic effects in the dog model. In both models, olodaterol provided bronchoprotection over 24 h. Formoterol applied at an equally effective dose did not retain efficacy over 24 h. In both models olodaterol showed a rapid onset of action comparable with formoterol. Taken together, the preclinical behavior of olodaterol suggests that this novel beta(2)-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile.PMID:
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