Molecular pharmacology
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Molecular pharmacology · Sep 2007
Comparative StudyDistinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
Selective modulation of alpha7 nicotinic acetylcholine receptors (nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target alpha7 nAChRs is by positive allosteric modulation. Structurally diverse compounds, including PNU-120596, 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), and 5-hydroxyindole (5-HI) have been identified as positive allosteric modulators (PAMs), but their receptor interactions and pharmacological profiles remain to be fully elucidated. ⋯ Both types of PAMs also increased the ACh-evoked alpha7 window currents, with type II PAMs generally showing larger potentiation. None of the PAMs tested increased nicotine-evoked Ca(2+) transients in human embryonic kidney 293 cells expressing human alpha4beta2 or alpha3beta4 nAChRs, although some inhibition was noted for 5-HI, genistein, and TQS. In summary, our studies reveal two distinct alpha7 PAM profiles, which could offer unique opportunities for modulating alpha7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.
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Molecular pharmacology · Sep 2007
The multikinase inhibitor sorafenib induces apoptosis in highly imatinib mesylate-resistant bcr/abl+ human leukemia cells in association with signal transducer and activator of transcription 5 inhibition and myeloid cell leukemia-1 down-regulation.
The effects of the multikinase inhibitor sorafenib (BAY 43-9006), an agent shown previously to induce apoptosis in human leukemia cells through inhibition of myeloid cell leukemia-1 (Mcl-1) translation, have been examined in Bcr/Abl(+) leukemia cells resistant to imatinib mesylate (IM). When administered at pharmacologically relevant concentrations (10-15 microM), sorafenib potently induced apoptosis in imatinib mesylate-resistant cells expressing high levels of Bcr/Abl, cells exhibiting a Bcr/Abl-independent, Lyn-dependent form of resistance, and CD34(+) cells obtained from imatinib-resistant patients. In addition, Ba/F3 cells expressing mutations rendering them resistant to IM (e.g., E255K, M351T) or to IM, dasatinib, and nilotinib (T315I) remained fully sensitive to sorafenib. ⋯ Ba/F3 cells expressing Bcr/Abl mutations were as sensitive to sorafenib-induced Mcl-1 down-regulation and dephosphorylation of STAT5 and eukaryotic initiation factor 4E as wild-type cells. Finally, stable knockdown of Bcl-2-interacting mediator of cell death (Bim) with short hairpin RNA in K562 cells significantly diminished sorafenib lethality, arguing strongly for a functional role of this proapoptotic Bcl-2 family member in the lethality of this agent. Together, these findings suggest that sorafenib effectively induces apoptosis in highly imatinib-resistant chronic myelogenous leukemia cells, most likely by inhibiting or down-regulating targets (i.e., STAT5 and Mcl-1) downstream or independent of Bcr/Abl.
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Molecular pharmacology · Sep 2007
Comparative StudyModulation of presynaptic beta3-containing GABAA receptors limits the immobilizing actions of GABAergic anesthetics.
Intravenous GABAergic anesthetics are potent hypnotics but are rather ineffective in depressing movements. Immobility is mediated, in part, by the ventral horn of the spinal cord. We hypothesized that the efficacy of these anesthetics in producing immobility is compromised by the activation of GABA(A) receptors located presynaptically, which modulate GABA release onto neurons in the ventral horn. ⋯ Etomidate prolonged the decay time of GABA(A) receptors at all tested concentrations. At concentrations greater than 1.0 microM, anesthetic-induced decrease of GABA release via modulation of presynaptic GABA(A) receptors and enhancement of postsynaptic GABA(A) receptor-function compensated for each other. The results suggest that the limited immobilizing efficacy of these agents is probably due to a presynaptic mechanism and that GABAergic agents with a specificity for post-versus presynaptic receptors would probably have much stronger immobilizing actions, pointing out novel avenues for drug development.