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- Ammoun, Sylwia, et al.
(författare)
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Distinct Recognition of OX1 and OX2 Receptors by Orexin Peptides
- 2003
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 305:2, s. 507-514
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we have compared the abilities of orexin-A and orexin-B and variants of orexin-A to activate different Ca(2+) responses (influx and release) in human OX(1) and OX(2) receptor- expressing Chinese hamster ovary cells. Responses mediated by activation of both receptor subtypes with either orexin-A or -B were primarily dependent on extracellular Ca(2+), suggesting similar activation of Ca(2+) influx as we have previously shown for orexin-A and OX(1) receptors. Amino acid-wise truncation of orexin-A reduced its ability to activate OX(1) and OX(2) receptors, but the response mediated by the OX(2) receptor was more resistant to truncation than the response mediated by the OX(1) receptor. We also performed a sequential replacement of amino acids 14 to 26 with alanine in the truncated orexin-A variant orexin-A(14-33). Replacement of the same amino acids produced a fall in the potency for each receptor subtype, but the reduction was less prominent for the OX(2) receptor. The most marked reduction was produced by the replacement of Leu20, Asp25, and His26 with alanine. Interestingly, extracellular Ca(2+) dependence of responses to some of the mutated peptides was different from those of orexin-A and -B. The mutagenesis also suggests that although the determinants required from orexin-A for binding to and activation of the receptor are highly conserved between the orexin receptor subtypes, the OX(2) receptor requires fewer determinants. This might in part explain why orexin-B has the affinity and potency equal to orexin-A for this subtype, although it has 10- to 100-fold lower affinity and potency for the OX(1) receptor.
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| 4. |
- Hassan, Saadia Bashir, et al.
(författare)
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Model for time dependency of the cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action
- 2001
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565 .- 1521-0103. ; 299:3, s. 1140-1147
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.
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| 10. |
- Linner, Love, et al.
(författare)
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Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex
- 2001
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565 .- 1521-0103. ; 297:2, s. 540-546
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Tidskriftsartikel (refereegranskat)abstract
- Central dopaminergic neurons have been suggested to be involved in the pathophysiology of several psychiatric disorders, including depression, and appear to be modulated by noradrenergic activity both at the nerve terminal level and at the somatodendritic level. In recent years reboxetine, a selective noradrenaline reuptake inhibitor that differs from tricyclic anti-depressants by its low affinity for muscarinic, cholinergic and α1-adrenergic receptors, has been introduced clinically. In the present study the effect of reboxetine on the function of the mesolimbocortical dopamine system was investigated by means of single cell recording and microdialysis in rats following administration of reboxetine in doses that appear to yield clinically relevant plasma concentrations. Reboxetine (0.625-20 mg/kg intravenously) induced an increase in burst firing, but not in average firing frequency of dopamine (DA) cells in the ventral tegmental area (VTA). Moreover, reboxetine (0.15-13.5 mg/kg intraperitoneally) caused a significantly enhanced DA output in the medial prefrontal cortex, whereas no effect was observed in the nucleus accumbens. Local administration of reboxetine (333 μM, 60 min), by means of reversed microdialysis into these brain regions, caused a significant increase in DA output in both brain regions. However, local administration of reboxetine into the VTA (333 μM, 60 min) did not affect DA availability in these terminal areas. Our results imply that clinical treatment with reboxetine may result in facilitation of both prefrontal DA output and the excitability of VTA DA neurons, effects that may contribute to its antidepressant action, especially on drive and motivation.
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