The Experts below are selected from a list of 5118 Experts worldwide ranked by ideXlab platform
Gage Peter - One of the best experts on this subject based on the ideXlab platform.
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Functional asymmetry of the conserved cystine loops in alphabetagamma GABA A receptors revealed by the response to GABA activation and Drug Potentiation
'Elsevier BV', 2015Co-Authors: Tierney Mary, Luu Tien, Gage PeterAbstract:Ligand-gated ion channels respond to specific neurotransmitters by transiently opening an integral membrane ion-selective pore, allowing ions to move down their electrochemical gradient. A distinguishing feature of all members of the ligand-gated ion channel superfamily is the presence of a 13-amino acid disulfide loop (Cys-loop) in the extracellular ligand-binding domain. Structural data derived from the acetylcholine receptor place this loop at the interface between the ligand-binding domain and the transmembrane pore-forming domain where it is ideally located to participate in coupling ligand binding to channel opening. We have introduced specific mutations into a conserved motif at the mid-point of the Cys-loop of the GABAA receptor subunits α1, β2 and γ2S where the sequence reads aromatic, proline, aliphatic (ArProAl motif). Receptors carrying a mutation in the Cys-loop of one of their subunits were expressed in L929 cells and responses to both GABA and Drugs were assessed using the whole-cell patch clamp technique. Drug Potentiation and direct activation were significantly enhanced by mutations in this Cys-loop but these effects were subunit-dependent. Currents in response to agonists were larger when mutations were carried in the α and β subunits but not in the γ subunit. In contrast, Potentiation of current responses by diazepam, etomidate and pentobarbital were all enhanced when mutations were carried in the α and γ subunits, but not the β subunit. Since the disruption of interactions mediated through the ArProAl motif enhances the mutant receptor's response to both agonist and Drugs we suggest that this motif in the Cys-loop of the wild-type receptor participates in interactions that create activation barriers to conformational changes during channel gating
A. A. Sosnova - One of the best experts on this subject based on the ideXlab platform.
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DEVELOPMENT OF COMPLEX PHARMACOTHERAPY OF SEVERE AND MODERATE PAIN. PART I. MULTITARGETED COMBINATION OF OPIOIDS AND NON-OPIOID ANALGESICS WITH CENTRAL EFFECTS
LLC Center of Pharmaceutical Analytics (LLC «CPHA»), 2019Co-Authors: A. V. Sosnov, F. M. Semchenko, M. I. Vlasov, V. N. Tohmahchi, A. A. SosnovaAbstract:Medicines based on opioid analgesics are the basic means of pharmacotherapy of severe pain at present. Approaches to increase efficacy and safety of complex opioid analgesia are described and classified based on analysis of medicinal and veterinary analgesics acting on different CNS biotargets. Principles of creation multitargeted fixed-dose combinations (FDC) and some schemes of multimodal analgesia are demonstrated by the example of opioid combinations with ligands of alpha-2 adrenergic receptors, antagonists of excitatory amino acid receptors, GABA ligands, their derivatives and analogues, cannabinoids, monoamines reuptake inhibitors and opiate receptor antagonists. Importance of multitargeted substances in general including coDrug approach for facilitating of Drug delivery and bioactivity enhancement were demonstrated. Development of opioid formulations with low level of dependency and tolerance and also principles to protect opioid formulations against non-medical use were described. Methodology of multitargeted analgesia is one of the drivers in Drug development on the background of low progress in the development of new effective molecules for relief of severe and moderate pain. The greatest interest is development of FDC with Drug Potentiation and efficacy at low doses. It allows creating wide variety of analgesics formulations
Tierney Mary - One of the best experts on this subject based on the ideXlab platform.
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Functional asymmetry of the conserved cystine loops in alphabetagamma GABA A receptors revealed by the response to GABA activation and Drug Potentiation
'Elsevier BV', 2015Co-Authors: Tierney Mary, Luu Tien, Gage PeterAbstract:Ligand-gated ion channels respond to specific neurotransmitters by transiently opening an integral membrane ion-selective pore, allowing ions to move down their electrochemical gradient. A distinguishing feature of all members of the ligand-gated ion channel superfamily is the presence of a 13-amino acid disulfide loop (Cys-loop) in the extracellular ligand-binding domain. Structural data derived from the acetylcholine receptor place this loop at the interface between the ligand-binding domain and the transmembrane pore-forming domain where it is ideally located to participate in coupling ligand binding to channel opening. We have introduced specific mutations into a conserved motif at the mid-point of the Cys-loop of the GABAA receptor subunits α1, β2 and γ2S where the sequence reads aromatic, proline, aliphatic (ArProAl motif). Receptors carrying a mutation in the Cys-loop of one of their subunits were expressed in L929 cells and responses to both GABA and Drugs were assessed using the whole-cell patch clamp technique. Drug Potentiation and direct activation were significantly enhanced by mutations in this Cys-loop but these effects were subunit-dependent. Currents in response to agonists were larger when mutations were carried in the α and β subunits but not in the γ subunit. In contrast, Potentiation of current responses by diazepam, etomidate and pentobarbital were all enhanced when mutations were carried in the α and γ subunits, but not the β subunit. Since the disruption of interactions mediated through the ArProAl motif enhances the mutant receptor's response to both agonist and Drugs we suggest that this motif in the Cys-loop of the wild-type receptor participates in interactions that create activation barriers to conformational changes during channel gating
Michael K Riscoe - One of the best experts on this subject based on the ideXlab platform.
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Potentiation of the antimalarial agent rufigallol
Antimicrobial Agents and Chemotherapy, 1996Co-Authors: R W Winter, Kenneth A Cornell, Linda L Johnson, Marina Ignatushchenko, David J Hinrichs, Michael K RiscoeAbstract:We have discovered a remarkable synergistic antimalarial interaction between rufigallol and the structurally similar compound exifone. The synergistic effects were produced in chloroquine-susceptible and chloroquine-resistant clones of Plasmodium falciparum. The degree of Potentiation as estimated by standard isobolar analysis was approximately 60-fold for experiments initiated with asynchronous parasites. The most pronounced synergism was observed in experiments with synchronized trophozoite-infected erythrocytes, in which the degree of synergy was at least 300-fold. While the mechanism underlying this Drug Potentiation remains unresolved, it is hypothesized that rufigallol acts in pro-oxidant fashion to produce oxygen radicals inside parasitized erythrocytes. These radicals would attack exifone, thereby initiating its transformation into a more potent compound, a xanthone.
A. V. Sosnov - One of the best experts on this subject based on the ideXlab platform.
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DEVELOPMENT OF COMPLEX PHARMACOTHERAPY OF SEVERE AND MODERATE PAIN. PART I. MULTITARGETED COMBINATION OF OPIOIDS AND NON-OPIOID ANALGESICS WITH CENTRAL EFFECTS
LLC Center of Pharmaceutical Analytics (LLC «CPHA»), 2019Co-Authors: A. V. Sosnov, F. M. Semchenko, M. I. Vlasov, V. N. Tohmahchi, A. A. SosnovaAbstract:Medicines based on opioid analgesics are the basic means of pharmacotherapy of severe pain at present. Approaches to increase efficacy and safety of complex opioid analgesia are described and classified based on analysis of medicinal and veterinary analgesics acting on different CNS biotargets. Principles of creation multitargeted fixed-dose combinations (FDC) and some schemes of multimodal analgesia are demonstrated by the example of opioid combinations with ligands of alpha-2 adrenergic receptors, antagonists of excitatory amino acid receptors, GABA ligands, their derivatives and analogues, cannabinoids, monoamines reuptake inhibitors and opiate receptor antagonists. Importance of multitargeted substances in general including coDrug approach for facilitating of Drug delivery and bioactivity enhancement were demonstrated. Development of opioid formulations with low level of dependency and tolerance and also principles to protect opioid formulations against non-medical use were described. Methodology of multitargeted analgesia is one of the drivers in Drug development on the background of low progress in the development of new effective molecules for relief of severe and moderate pain. The greatest interest is development of FDC with Drug Potentiation and efficacy at low doses. It allows creating wide variety of analgesics formulations
