43 results on '"Thomas F. Murray"'
Search Results
2. Biogenic Amine Transmitters
- Author
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Thomas F. Murray
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Norepinephrine (medication) ,chemistry.chemical_classification ,chemistry.chemical_compound ,Materials science ,chemistry ,Dopamine ,Biogenic amine ,Cholinergic neurotransmission ,medicine ,Pharmacology ,Acetylcholinesterase ,Acetylcholine ,medicine.drug - Published
- 2019
3. Neuropeptides
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Thomas F. Murray
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medicine.medical_specialty ,Endocrinology ,Oxytocin ,business.industry ,Internal medicine ,medicine ,Neuropeptide ,business ,medicine.drug - Published
- 2019
4. Amino Acid Neurotransmitters
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Thomas F. Murray
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chemistry.chemical_classification ,Biochemistry ,Chemistry ,Aspartic acid ,Glycine ,medicine ,Glutamic acid ,gamma-Aminobutyric acid ,Amino acid ,medicine.drug - Published
- 2019
5. Biogenic Amine Neurotransmitters
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Thomas F. Murray
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chemistry.chemical_classification ,Norepinephrine (medication) ,medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,Biogenic amine ,Monoaminergic ,medicine ,Serotonin ,Receptor ,medicine.drug - Published
- 2019
6. General Principles of Psychopharmacology
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Thomas F. Murray
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medicine.anatomical_structure ,business.industry ,Central nervous system ,Dose dependence ,Medicine ,Drug action ,Psychopharmacology ,Chemical neurotransmission ,business ,Neuroscience - Published
- 2019
7. Veterinary Psychopharmacology
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Sharon L. Crowell‐Davis, Thomas F. Murray, and Leticia Mattos Dantas
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- 2019
8. Binding and Signaling Properties of the Leu 8 and Pro 8 Isoforms of Oxytocin for Oxytocin Receptors from Four Primate Species
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Nancy A. Schulte, Jack H. Taylor, Jeffrey A. French, Thomas F. Murray, and Myron L. Toews
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Gene isoform ,biology ,Chemistry ,Biochemistry ,Oxytocin receptor ,Cell biology ,Oxytocin ,biology.animal ,Genetics ,medicine ,Primate ,Molecular Biology ,Biotechnology ,medicine.drug - Published
- 2018
9. VOLTAGE‐GATED SODIUM CHANNEL ACTIVATION TRIGGERS CALCIUM INFLUX AND HIPPOCAMPAL NEURON COMPLEXITY
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Thomas F. Murray and Dina Gomez
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Chemistry ,Sodium channel ,Genetics ,Biophysics ,Hippocampal neuron ,Molecular Biology ,Biochemistry ,Calcium influx ,Biotechnology - Published
- 2018
10. Comprehensive Study on the Potential Therapeutic Use of Brevetoxin‐2 to Aid Post‐stroke Recovery
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Marsha L. Pierce, Thomas F. Murray, Erica Sequeira, and Dina Gomez
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Brevetoxin ,medicine.medical_specialty ,business.industry ,Emergency medicine ,Genetics ,Post stroke ,Medicine ,business ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2018
11. Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour
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Thomas F. Murray, Jane V. Aldrich, Nicolette C. Ross, Michelle L. Ganno, Shainnel O. Eans, Jay P. McLaughlin, K A Reilley, and Sanjeewa N. Senadheera
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Pharmacology ,medicine.drug_class ,Antagonist ,chemistry.chemical_compound ,chemistry ,Opioid ,In vivo ,Opioid receptor ,medicine ,Peptide synthesis ,Receptor ,Opioid antagonist ,Receptor antagonist activity ,medicine.drug - Abstract
Background and Purpose The novel macrocyclic peptide cyclo[Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. Experimental Approach The peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. Key Results The alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and μ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28–4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine- and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. Conclusions and Implications These unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics.
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- 2014
12. Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting κ opioid receptor antagonism
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Kate J. Reilley, Thomas F. Murray, Jay P. McLaughlin, Nicolette C. Ross, and Jane V. Aldrich
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Pharmacology ,Agonist ,Tetrapeptide ,medicine.drug_class ,Chemistry ,Antagonist ,Conditioned place preference ,Opioid ,Opioid receptor ,medicine ,Radioligand ,Antagonism ,medicine.drug - Abstract
BACKGROUND AND PURPOSE The κ opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non-peptide κ-receptor selective antagonists show exceptionally long activity. We hypothesized that the L- and D-Trp isomers of CJ-15,208, a natural cyclic tetrapeptide reported to be a κ-receptor antagonist in vitro, would demonstrate short-acting, dose-dependent antagonism in vivo, preventing reinstatement of cocaine-seeking behaviour. EXPERIMENTAL APPROACH Affinity, selectivity and efficacy of the L-Trp and D-Trp isomers for opioid receptors were assessed in vitro in radioligand and GTPγS binding assays. Opioid receptor agonist and antagonist activities were characterized in vivo following i.c.v. administration with the 55°C warm water tail-withdrawal assay. The D-Trp isomer, which demonstrated primarily κ-receptor selective antagonist activity, was further evaluated for its prevention of stress- and drug-induced reinstatement of extinguished cocaine conditioned place preference (CPP). KEY RESULTS The two isomers showed similar affinity and selectivity for κ receptors (Ki 30–35 nM) as well as κ receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent κ-receptor selective antagonism lasting less than 18 h in vivo. Pretreatment with this peptide prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine CPP. In contrast, the L-Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist/antagonist activity. CONCLUSIONS AND IMPLICATIONS The L-Trp and the D-Trp isomers of CJ-15,208 demonstrate stereospecific opioid activity in vivo. The relatively brief κ opioid receptor antagonism, coupled with the prevention of stress-induced reinstatement of extinguished cocaine-seeking behaviour, suggests the D-Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse.
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- 2012
13. Deletion of Ac-NMePhe1 from [NMePhe1]arodyn under acidic conditions, part 2: Effects of substitutions on pharmacological activity
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Jane V. Aldrich, Wei Jie Fang, Marco A. Bennett, and Thomas F. Murray
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Spectrometry, Mass, Electrospray Ionization ,Stereochemistry ,medicine.drug_class ,Phenylalanine ,Biophysics ,CHO Cells ,Dynorphin ,Binding, Competitive ,Dynorphins ,Methylation ,Biochemistry ,Article ,Biomaterials ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cricetulus ,Opioid receptor ,Cricetinae ,medicine ,Animals ,Structure–activity relationship ,Amino Acid Sequence ,Amino Acids ,Receptor ,Chromatography, High Pressure Liquid ,Molecular Structure ,Receptors, Opioid, kappa ,Organic Chemistry ,Tryptophan ,Antagonist ,Dynorphin A ,Biological activity ,General Medicine ,Rats ,Models, Chemical ,chemistry ,Opioid ,Tyrosine ,Peptides ,Acids ,Protein Binding ,medicine.drug - Abstract
Arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]Dyn A(1-11)-NH2) is an acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J. Med. Chem. 2002, 45, 5617), and its analog [NMePhe1]arodyn shows even higher affinity and selectivity for κ opioid receptors (Bennett et al., J. Pep. Res. 2005, 65, 322). However, the latter compound is prone to deletion of the Ac-NMePhe moiety from the N-terminus of the peptide during acidic cleavage as described in the accompanying paper. Several stable analogs of [NMePhe1]arodyn and [NMePhe1,Trp3]arodyn where the acetyl group was substituted with a heteroatom-containing group were evaluated for their opioid receptor affinity, selectivity, and efficacy. Methoxycarbonyl derivatives exhibited the highest κ opioid receptor affinity among the analogs. Additional CH3OCO[NMePhe1]arodyn analogs where position 3 was substituted with other aromatic or non-aromatic residues were also evaluated for κ receptor affinity, selectivity, and efficacy. [CH3OCO-NMePhe1]arodyn has similar κ opioid receptor affinity as [NMePhe1]arodyn, retains high κ opioid receptor selectivity, and is a potent κ opioid receptor antagonist.
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- 2011
14. Synthesis and opioid activity of 2-substituted dynorphin A-(1-13) amide analogues1
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Gary E. DeLander, Thomas F. Murray, Sandra Story, and Jane V. Aldrich
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chemistry.chemical_classification ,Stereochemistry ,medicine.drug_class ,Ligand binding assay ,Dynorphin A ,Dynorphin ,Biochemistry ,κ-opioid receptor ,Amino acid ,chemistry.chemical_compound ,chemistry ,Opioid receptor ,Peptide synthesis ,medicine ,μ-opioid receptor - Abstract
A series of 2-substituted dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) analogues was prepared by solid phase peptide synthesis and evaluated for opioid receptor affinities in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI) assay. Amino acid substitution at the 2 position produced marked differences in both opioid receptor affinities and potency in the GPI assay; Ki values for the analogues in the radioligand binding assays and IC50 values in the GPI assay varied over three to four orders of magnitude. The parent peptide, Dyn A-(1-13)NH2, exhibited the greatest affinity and selectivity for kappa receptors and was the most potent peptide examined in the GPI assay. The most important determinant of opioid receptor selectivity and opioid potency for the synthetic analogues was the stereochemistry of the amino acid at the 2 position. Except for [D-Lys2]Dyn A-(1-13)NH2 in the kappa receptor binding assay, the analogues containing a D-amino acid at position 2 were much more potent in all of the assays than their corresponding isomers containing an L-amino acid at this position. The L-amino acid-substituted analogues generally retained some selectivity for kappa opioid receptors. The more potent derivatives with a D-amino acid in position 2, however, preferentially interacted with mu opioid receptors. Introduction of a positively charged amino acid into the 2 position generally decreased opioid receptor affinities and potency in the GPI assay.
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- 2009
15. Synthesis and evaluation of potential affinity labels derived from endomorphin-2
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Thomas F. Murray, Jane V. Aldrich, and H. Choi
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chemistry.chemical_classification ,biology ,Tetrapeptide ,Stereochemistry ,Affinity label ,Chinese hamster ovary cell ,Peptide ,Biochemistry ,Combinatorial chemistry ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Isothiocyanate ,biology.protein ,Peptide synthesis ,Receptor ,IC50 - Abstract
In an attempt to identify potential peptide-based affinity labels for opioid receptors, endomorphin-2 (Tyr-Pro-Phe-PheNH2), a potent and selective endogenous ligand for mu-opioid receptors, was chosen as the parent peptide for modification. The tetrapeptide analogs were prepared using standard Fmoc-solid phase peptide synthesis in conjunction with incorporation of Fmoc-Phe(p-NHAlloc) and modification of the p-amino group. The electrophilic groups isothiocyanate and bromoacetamide were introduced into the para position on either Phe3 or Phe4; the corresponding free amine-containing peptides were also prepared for comparison. The peptides bearing an affinity label group and their free amine analogs were evaluated in a radioligand-binding assay using Chinese hamster ovary (CHO) cells expressing mu- and delta-opioid receptors. Modification on Phe4 was better tolerated than on Phe3 for mu-receptor binding. Among the analogs tested, [Phe(p-NH2)4]endomorphin-2 showed the highest affinity (IC50 = 37 nm) for mu-receptors. The Phe(p-NHCOCH2Br)4 analog displayed the highest mu-receptor affinity (IC50 = 158 nm) among the peptides containing an affinity label group. Most of the compounds exhibited negligible binding affinity for delta-receptors, similar to the parent peptide.
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- 2008
16. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block
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Jeremy Barber, Thomas F. Murray, Hongjie Yuan, Cara Mosley, Polina Lyuboslavsky, Katherine L. Nicholson, Shashank M. Dravid, Antoine G. Almonte, Robert L. Balster, Phuong Le, Adam French, Kevin Erreger, Stephen F. Traynelis, and Ernest E. Murray
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Agonist ,Physiology ,Chemistry ,Stereochemistry ,medicine.drug_class ,Allosteric regulation ,Gating ,TRPC1 ,Dizocilpine ,nervous system ,medicine ,NMDA receptor ,Channel blocker ,Ion channel ,medicine.drug - Abstract
We have compared the potencies of structurally distinct channel blockers at recombinant NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D receptors. The IC50 values varied with stereochemistry and subunit composition, suggesting that it may be possible to design subunit-selective channel blockers. For dizocilpine (MK-801), the differential potency of MK-801 stereoisomers determined at recombinant NMDA receptors was confirmed at native receptors in vitro and in vivo. Since the proton sensor is tightly linked both structurally and functionally to channel gating, we examined whether blocking molecules that interact in the channel pore with the gating machinery can differentially sense protonation of the receptor. Blockers capable of remaining trapped in the pore during agonist unbinding showed the strongest dependence on extracellular pH, appearing more potent at acidic pH values that promote channel closure. Determination of pKa values for channel blockers suggests that the ionization of ketamine but not of other blockers can influence its pH-dependent potency. Kinetic modelling and single channel studies suggest that the pH-dependent block of NR1/NR2A by (−)MK-801 but not (+)MK-801 reflects an increase in the MK-801 association rate even though protons reduce channel open probability and thus MK-801 access to its binding site. Allosteric modulators that alter pH sensitivity alter the potency of MK-801, supporting the interpretation that the pH sensitivity of MK-801 binding reflects the changes at the proton sensor rather than a secondary effect of pH. These data suggest a tight coupling between the proton sensor and the ion channel gate as well as unique subunit-specific mechanisms of channel block.
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- 2007
17. Activation of Voltage‐Gated Sodium Channels with Brevetoxin‐2 (PbTx‐2) Increases Dendritic Spine Density in Murine Organotypic Hippocampal Slice Culture
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Thomas F. Murray and Dina Gomez
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animal structures ,Dendritic spine ,endocrine system diseases ,Neurite ,Voltage-gated ion channel ,Chemistry ,Sodium channel ,Sodium ,fungi ,nutritional and metabolic diseases ,chemistry.chemical_element ,Anatomy ,Biochemistry ,Brevetoxin ,nervous system ,Genetics ,Biophysics ,NMDA receptor ,Receptor ,Molecular Biology ,Biotechnology - Abstract
The N-methyl-D-aspartate receptor (NMDAR) is essential for activity-dependent neurite outgrowth, dendritic arborization and spine formation. We previously demonstrated that the voltage gated sodium...
- Published
- 2015
18. Cloning and pharmacological characterization of the equine adenosine A2A receptor: a potential therapeutic target for the treatment of equine endotoxemia
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Michel L. Vandenplas, C. I. Brandon, Thomas F. Murray, H. Dookwah, and Joel Linden
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Agonist ,Adenosine ,DNA, Complementary ,Receptor, Adenosine A2A ,medicine.drug_class ,Molecular Sequence Data ,Adenosine A2A receptor ,Biology ,Pharmacology ,Transfection ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Horses ,Cloning, Molecular ,Receptor ,Reporter gene ,Binding Sites ,Expression vector ,General Veterinary ,HEK 293 cells ,Molecular biology ,Endotoxemia ,Horse Diseases ,Heterologous expression - Abstract
The aim of the current study was to clone the equine adenosine A(2A) receptor gene and to establish a heterologous expression system to ascertain its pharmacologic profile via radioligand binding and functional assays. An eA(2A)-R expression construct was generated by ligation of the eA(2A) cDNA into the pcDNA3.1 expression vector, and stably transfected into human embryonic kidney cells (HEK). Binding assays identified those clones expressing the eA(2A)-R, and equilibrium saturation isotherm experiments were utilized to determine dissociation constants (K(D)), and receptor densities (B(max)) of selected clones. Equilibrium competition binding revealed a rank order of agonist potency of ATL > CV-1808 > NECA > 2-CADO > CGS21680, and a rank order of antagonist potency as ZM241385 > 8-phenyltheophylline > p-sulfophenyltheophylline > caffeine. Furthermore, adenylate cyclase assays using selective A(2A)-R agonists revealed that the eA(2A)-R functionally coupled to Galpha(s) as indicated by an increase in intracellular [(3)H]cAMP upon receptor activation. Finally, NF-kappaB reporter gene assays revealed a CGS21680 concentration-dependent inhibition of NF-kappaB activity. These results indicate that the heterologously expressed eA(2A)-R has a pharmacological profile similar to that of other mammalian A(2A) receptors and thus can be utilized for further characterization of the eA(2A)-R to ascertain whether it can serve as a suitable pharmacological target for equine inflammatory disease.
- Published
- 2006
19. Brevetoxin activation of voltage-gated sodium channels regulates Ca2+ dynamics and ERK1/2 phosphorylation in murine neocortical neurons
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Thomas F. Murray, Shashank M. Dravid, and Daniel G. Baden
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Neurotoxins ,Allosteric regulation ,Glutamic Acid ,Neocortex ,Biology ,Biochemistry ,Article ,Sodium Channels ,Mice ,Cellular and Molecular Neuroscience ,Brevetoxin ,medicine ,Animals ,Neurotoxin ,Calcium Signaling ,Enzyme Inhibitors ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,Cells, Cultured ,Calcium signaling ,Mitogen-Activated Protein Kinase 1 ,Neurons ,Mitogen-Activated Protein Kinase 3 ,Brain-Derived Neurotrophic Factor ,Sodium channel ,Oxocins ,Enzymes ,medicine.anatomical_structure ,Biophysics ,Calcium ,Marine Toxins ,Neuron ,Mitogen-Activated Protein Kinases ,Excitatory Amino Acid Antagonists ,Ion Channel Gating ,Neuroscience ,Marine toxin - Abstract
Voltage-gated sodium channels (VGSC) are involved in the generation of action potentials in neurons. Brevetoxins (PbTx) are potent allosteric enhancers of VGSC function and are associated with the periodic 'red tide' blooms. Using PbTx-2 as a probe, we have characterized the effects of activation of VGSC on Ca(2+) dynamics and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling in neocortical neurons. Neocortical neurons exhibit synchronized spontaneous Ca(2+) oscillations, which are mediated by glutamatergic signaling. PbTx-2 (100 nm) increased the amplitude and reduced the frequency of basal Ca(2+) oscillations. This modulatory effect on Ca(2+) oscillations produced a sustained rise in ERK1/2 activation. At 300 nm, PbTx-2 disrupted oscillatory activity leading to a sustained increase in intracellular Ca(2+) ([Ca(2+)](i)) and induced a biphasic, activation followed by dephosphorylation, regulation of ERK1/2. PbTx-2-induced ERK1/2 activation was Ca(2+) dependent and was mediated by Ca(2+) entry through manifold routes. PbTx-2 treatment also increased cAMP responsive element binding protein (CREB) phosphorylation and increased gene expression of brain-derived neurotrophic factor (BDNF). These findings indicate that brevetoxins, by influencing the activation of key signaling proteins, can alter physiologic events involved in survival in neocortical neurons, as well as forms of synaptic plasticity associated with development and learning.
- Published
- 2004
20. Synthesis and evaluation of derivatives of leucine enkephalin as potential affinity labels for δ opioid receptors
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Jane V. Aldrich, Heekyung Choi, and Thomas F. Murray
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Enkephalin ,Stereochemistry ,Affinity label ,Receptors, Opioid, mu ,Biophysics ,Peptide ,CHO Cells ,Biochemistry ,Biomaterials ,δ-opioid receptor ,Radioligand Assay ,chemistry.chemical_compound ,Cricetinae ,Receptors, Opioid, delta ,Peptide synthesis ,Animals ,Receptor ,Opioid peptide ,chemistry.chemical_classification ,Staining and Labeling ,biology ,Organic Chemistry ,Affinity Labels ,General Medicine ,chemistry ,biology.protein ,Enkephalin, Leucine - Abstract
As part of an effort to develop peptide-based affinity labels for opioid receptors, [Leu(5)]enkephalin (LeuEnk) and DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr), potent agonists for delta receptors, were selected as the parent peptides for further modification. The affinity label derivatives were prepared using standard Fmoc solid-phase peptide synthesis in conjunction with Fmoc-Phe(p-NHAlloc) (Fmoc: 9-flourenylmethoxycarbonyl;) and selective modification of the p-amino group on this residue. The electrophilic isothiocyanate and bromoacetamide groups were introduced into the para position of Phe(4); the corresponding free amine-containing peptides were also prepared for comparison. The pure peptides were evaluated in radioligand binding assays using Chinese hamster ovary (CHO) cells expressing delta and micro opioid receptors. Modification of Phe(4) in LeuEnk and DTLET significantly decreased delta-receptor binding affinity (40 to >2,000-fold). Among the synthesized analogues, [Phe(p-NH(2))(4)]DTLET showed the highest delta-receptor binding affinity (IC(50) = 39 nM) and enhanced selectivity for delta receptors compared to DTLET while other derivatives exhibited much lower delta receptor affinity. The differences in affinities between the two series of analogues and between the derivatives of LeuEnk and N,N-dibenzyl[Leu(5)]Enk reported previously suggest subtle differences in interactions of Phe(4) with delta receptors depending on other modifications in the sequences.
- Published
- 2003
21. Synthesis of novel basic head-to-side-chain cyclic dynorphin A analogs: Strategies and side reactions
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Thomas F. Murray, Jane V. Aldrich, and Balvinder S. Vig
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chemistry.chemical_classification ,Stereochemistry ,Organic Chemistry ,Biophysics ,Dynorphin A ,Peptide ,CHO Cells ,General Medicine ,Alkylation ,Dynorphins ,Peptides, Cyclic ,Biochemistry ,Cyclic peptide ,Biomaterials ,chemistry.chemical_compound ,chemistry ,Cricetinae ,Receptors, Opioid ,Side chain ,Animals ,Amine gas treating ,Protecting group ,Opioid peptide - Abstract
Novel N-terminus-to-side-chain cyclic analogs of the opioid peptide dynorphin (Dyn) A-(1-11)NH(2) were prepared that retain the basicity of the N-terminal amine and restrict the backbone conformation around the important Tyr(1) residue. Cyclic peptides were synthesized in which the N-terminal amine and the N(epsilon)-amine of a Lys at position 3 or 5 were attached to the alpha-carbon and carbonyl of an acetyl group, respectively. Several synthetic strategies were explored with detailed analysis of the side reactions in order to obtain the desired cyclic peptides. One of the side reactions observed involved premature loss of the N-terminal 9-fluorenylmethoxycarbonyl (Fmoc) group during the neutralization step following deprotection of the Mtt (4-methyltrityl) protecting group from the side chain of Lys. The successful strategy involved the synthesis of the linear peptide up through Gly(2) and functionalization through the N(epsilon)-amine of Lys. A linear N-terminal alkylated analog was prepared by alkylation of the peptide on the resin with an equimolar amount of bromoacetamide, followed by treatment of the peptide with Fmoc-OSu prior to cleavage from the resin to facilitate separation by reversed phase high performance liquid chromatography of unreacted peptide from the desired alkylated product. The novel N-terminal cyclic Dyn A analogs and the linear analog were evaluated for their opioid receptor affinities. These peptides exhibited large losses in affinity for opioid receptors; the low affinity of the linear N-terminal alkylated peptide suggested that the alpha-acetamide group on the N-terminal amine resulted in unfavorable interactions with opioid receptors.
- Published
- 2003
22. Dermorphin-based potential affinity labels for µ-opioid receptors*
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H. Choi, Thomas F. Murray, and Jane V. Aldrich
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chemistry.chemical_classification ,biology ,Stereochemistry ,medicine.drug_class ,Chemistry ,Affinity label ,Chinese hamster ovary cell ,Peptide ,Dermorphin ,Biochemistry ,Combinatorial chemistry ,DAMGO ,chemistry.chemical_compound ,Endocrinology ,Opioid receptor ,biology.protein ,medicine ,μ-opioid receptor ,Receptor - Abstract
Dermorphin and [Lys7]dermorphin, selective micro -opioid receptor ligands originating from amphibian skin, have been modified with various electrophiles in either the 'message' or 'address' sequences as potential peptide-based affinity labels for micro -receptors. Introduction of the electrophilic isothiocyanate and bromoacetamide groups on the para position of Phe3 and Phe5 was accomplished by incorporating Fmoc-Phe(p-NHAlloc) into the peptide followed by selective deprotection and modification. The corresponding amine-containing peptides were also prepared. The pure peptides were evaluated in radioligand binding experiments using Chinese hamster ovary (CHO) cells expressing micro - and delta-opioid receptors. In dermorphin, introduction of the electrophilic groups in the 'message' domain lowered the binding affinity by > 1000-fold; only [Phe(p-NH2)3]dermorphin retained nanomolar affinity for micro -receptors. Modifications in the 'address' region of both dermorphin and [Lys7]dermorphin were relatively well tolerated. In particular, [Phe(p-NH2)5,Lys7]dermorphin showed similar affinity to dermorphin, with almost 2-fold higher selectivity for micro -receptors. [Phe(p-NHCOCH2Br)5]- and [Phe(p-NHCOCH2Br)5,Lys7]dermorphin exhibited relatively high affinity (IC50 = 27.7 and 15.1 nm, respectively) for micro -receptors. However, neither of these peptides inhibited [3H]DAMGO binding in a wash-resistant manner.
- Published
- 2002
23. High Level Expression of the NMDAR1 Glutamate Receptor Subunit in Electroporated COS Cells
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Thomas F. Murray, Mark Leid, Jane E. Ishmael, and Paul H. Franklin
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Fura-2 ,Macromolecular Substances ,Recombinant Fusion Proteins ,Glycine ,Biology ,Kidney ,Kynurenic Acid ,Transfection ,Binding, Competitive ,Receptors, N-Methyl-D-Aspartate ,Biochemistry ,Cell Line ,Radioligand Assay ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Glycine binding ,Chlorocebus aethiops ,Serine ,Animals ,Humans ,Homomeric ,Receptor ,COS cells ,HEK 293 cells ,Stereoisomerism ,beta-Galactosidase ,Molecular biology ,Rats ,Kinetics ,Electroporation ,chemistry ,COS Cells ,NMDA receptor ,Calcium ,Excitatory Amino Acid Antagonists - Abstract
The rat N-methyl-D-aspartate (NMDA) glutamate receptor subunit NR1-1a was transiently expressed in COS cells using the technique of electroporation, which was fivefold more efficient than the calcium phosphate precipitation method of transfection. The glycine site antagonist 5,7-[3H]dichlorokynurenic acid labeled a single high-affinity site (K D = 29.6 ± 6 nM ; B max = 19.4 ± 1.6 pmol/mg of protein) in membranes derived from COS cells electroporated with NR1-1a. In contrast to previous reports using transiently transfected human embryonic kidney 293 cells, binding of the noncompetitive antagonist (+)-5-[ 3 H]methyl-10,11-dihydro-5H-dibenzo [a,d]-cyclohepten-5,10-imine ([ 3 H]MK-801) was not detected in NRI-1a-transfected COS cells. Although immunofluorescent labeling of electroporated COS cells demonstrated that the NRI-1a protein appears to be associated with the cell membrane, neither NMDA nor glutamate effected an increase in intracellular calcium concentration in fura-2-loaded cells, suggesting that homomeric NR1-1a receptors do not act as functional ligand-gated ion channels. Therefore, COS cells appear to differ from Xenopus oocytes with respect to the transient expression of functional homomeric NR1 receptors. Although expression of NR1-1 is sufficient to reconstitute a glycine binding site with wild-type affinity for antagonists in COS cells, recombinant homomeric NR1-1 receptors do not display properties that are characteristic of native NMDA receptors, such as permeability to Ca 2+ and channel occupancy by MK-801, when expressed in this mammalian cell line.
- Published
- 2002
24. Chronic Exposure to Adenosine Receptor Agonists and Antagonists Reciprocally Regulates the A1 Adenosine Receptor-Adenylyl Cyclase System in Cerebellar Granule Cells
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Thomas F. Murray, Barbara D. Hettinger-Smith, and Mark Leid
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medicine.medical_specialty ,Adenosine ,Time Factors ,2-Chloroadenosine ,4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone ,Biology ,Adenosine receptor antagonist ,Binding, Competitive ,Biochemistry ,Rats, Sprague-Dawley ,Adenylyl cyclase ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Adenosine A1 receptor ,Theophylline ,GTP-Binding Proteins ,Cerebellum ,Internal medicine ,Purinergic P1 Receptor Agonists ,medicine ,Animals ,Neurons ,Guanylyl Imidodiphosphate ,Cell Membrane ,Receptors, Purinergic P1 ,Purinergic signalling ,Adenosine A3 receptor ,Adenosine receptor ,Rats ,Kinetics ,Endocrinology ,Purinergic P1 Receptor Antagonists ,chemistry ,Xanthines ,Phenylisopropyladenosine ,Adenosine A2B receptor ,Adenylyl Cyclases ,medicine.drug - Abstract
Chronic treatment with the adenosine receptor antagonist caffeine evokes an up-regulation of A1 adenosine receptors and increased coupling of the receptor to G proteins in rat brain membranes. However, chronic agonist exposure has not been explored. Primary cultures of cerebellar granule cells were exposed chronically to A1 adenosine receptor agonists and antagonists. Exposure to the A1 adenosine receptor agonist N6-cyclopentyladenosine resulted in (1) a time- and concentration-dependent reduction in the density of receptors labeled by 1,3-[3H]dipropyl-8-cyclopentylxanthine, (2) an enhanced ability of guanyl nucleotides to decrease the fraction of A1 adenosine receptor sites displaying high affinity for 2-chloroadenosine, and (3) a functional uncoupling of receptors from adenylyl cyclase (EC 4.6.1.1). The adenosine antagonists caffeine and 8-p-sulfophenyltheophylline produced alterations in A1 adenosine receptor homeostasis that were antipodal to those associated with agonist treatment. Antagonist exposure (1) increased the density of A1 adenosine receptors in cerebellar granule cell membranes, (2) blunted the effect of guanyl nucleotides on receptor coupling to G proteins, and (3) increased the functional coupling of receptors to adenylyl cyclase inhibition. Forskolin treatment of cerebellar granule cells did not affect receptor density, suggesting that cyclic AMP is not involved in the regulation of A1 adenosine receptor expression.
- Published
- 2002
25. Cyclopentyladenosine-Induced Homologous Down-Regulation of A1 Adenosine Receptors (A1AR) in Intact Neurons Is Accompanied by Receptor Sequestration but Not a Reduction in A1AR mRNA Expression or G Protein α-Subunit Content
- Author
-
Mark Leid, Thomas F. Murray, and Barbara D. Hettinger
- Subjects
Agonist ,medicine.medical_specialty ,Adenosine ,G protein ,medicine.drug_class ,Down-Regulation ,Gene Expression ,Biology ,Tritium ,Adenosine receptor antagonist ,Biochemistry ,Rats, Sprague-Dawley ,Adenylyl cyclase ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Adenosine deaminase ,Theophylline ,Cerebellum ,Internal medicine ,GTP-Binding Protein alpha Subunits, Gs ,Purinergic P1 Receptor Agonists ,medicine ,Animals ,RNA, Messenger ,Receptor ,Cells, Cultured ,Neurons ,Receptors, Purinergic P1 ,Adenosine receptor ,Rats ,Endocrinology ,chemistry ,Xanthines ,Adenylyl Cyclase Inhibitors ,biology.protein ,Adenylyl Cyclases ,medicine.drug - Abstract
We showed previously that exposure of cerebellar granule cells to the A 1 adenosine receptor (A 1 AR)-selective agonist, cyclopentyladenosine, decreases A 1 AR density and G protein coupling corresponding to blunted agonist-induced adenylyl cyclase (EC 4.6.1.1) inhibition. We have now determined that A 1 AR-mediated adenylyl cyclase inhibition was desensitized in a homologous manner. Carbachol- and baclofen-induced inhibition of adenylyl cyclase was unaffected by 48-h exposure to 10 μM cyclopentyladenosine. Expression of G protein α-subunits was not affected dramatically by agonist exposure. The fraction of sequestered A 1 AR was increased significantly at 4, 24, and 48 h of cyclopentyladenosine exposure (35, 57, and 81 % increase over control, respectively). The time course of agonist-induced A 1 AR sequestration was slower than that reported for other G protein-coupled receptors. Incubation with the adenosine receptor antagonist, 8-p-sulfophenyltheophylline or adenosine deaminase did not alter sequestration significantly. Neither steady-state A 1 AR mRNA levels nor transcript stability was affected by 48-h agonist exposure. We determined that A 1 AR half-life in cerebellar granule cells is 20.9 h, which is considerably longer than that reported for several other G protein-coupled receptors. The slow time course of A 1 AR sequestration and the stability of the corresponding mRNA may be a reflection of the tonic inhibitory tone exerted by adenosine in brain.
- Published
- 2002
26. Alanine scan of the opioid peptide dynorphin B amide
- Author
-
Thomas F. Murray, Anand A. Joshi, and Jane V. Aldrich
- Subjects
0301 basic medicine ,Agonist ,endocrine system ,medicine.drug_class ,Stereochemistry ,Biophysics ,CHO Cells ,Dynorphin ,Dynorphins ,Biochemistry ,κ-opioid receptor ,Article ,Biomaterials ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,0302 clinical medicine ,Opioid receptor ,Cricetinae ,medicine ,Peptide synthesis ,Animals ,Amino Acid Sequence ,Endorphins ,Opioid peptide ,Solid-Phase Synthesis Techniques ,Alanine ,Receptors, Opioid, kappa ,Organic Chemistry ,Dynorphin B ,General Medicine ,respiratory system ,Amides ,030104 developmental biology ,Opioid Peptides ,chemistry ,Mutagenesis ,embryonic structures ,030217 neurology & neurosurgery ,Protein Binding ,circulatory and respiratory physiology - Abstract
To date structure-activity relationship (SAR) studies of the dynorphins (Dyn), endogenous peptides for kappa opioid receptors (KOR), have focused almost exclusively on Dyn A with minimal studies on Dyn B. While both Dyn A and Dyn B have identical N-terminal sequences, their C-terminal sequences differ, which could result in differences in pharmacological activity. We performed an alanine scan of the non-glycine residues up through residue 11 of Dyn B amide to explore the roles of these side chains in the activity of Dyn B. The analogs were synthesized by fluorenylmethyloxycarbonyl (Fmoc)-based solid phase peptide synthesis and evaluated for their opioid receptor affinities and opioid potency and efficacy at KOR. Similar to Dyn A the N-terminal Tyr1 and Phe4 residues of Dyn B amide are critical for opioid receptor affinity and KOR agonist potency. The basic residues Arg6 and Arg7 contribute to the KOR affinity and agonist potency of Dyn B amide, while Lys10 contributes to the opioid receptor affinity, but not KOR agonist potency, of this peptide. Comparison to the Ala analogs of Dyn A (1-13) suggests that the basic residues in the C-terminus of both peptides contribute to KOR binding, but differences in their relative positions may contribute to the different pharmacological profiles of Dyn A and Dyn B. The other unique C-terminal residues in Dyn B amide also appear to influence the relative affinity of this peptide for KOR versus mu and delta opioid receptors. This SAR information may be applied in the design of new Dyn B analogs that could be useful pharmacological tools.
- Published
- 2017
27. Dynorphin A analogs containing a conformationally constrained phenylalanine derivative in position 4: Reversal of preferred stereochemistry for opioid receptor affinity and discrimination of ? vs. ? receptors
- Author
-
Qi Zheng, Thomas F. Murray, and Jane V. Aldrich
- Subjects
Pharmacology ,chemistry.chemical_classification ,Stereochemistry ,Chemistry ,medicine.drug_class ,Organic Chemistry ,Dynorphin A ,Peptide ,Dynorphin ,Catalysis ,Analytical Chemistry ,δ-opioid receptor ,chemistry.chemical_compound ,Opioid receptor ,Drug Discovery ,medicine ,μ-opioid receptor ,Opioid peptide ,Receptor ,Spectroscopy - Abstract
Analogs of the opioid peptide [D-Ala8]dynorphin A-(1-11)NH2 containing optically pure (R)- and (S)-2-aminotetralin-2-carboxylic acid (Atc) in position 4 were synthesized and evaluated for opioid receptor affinity. These peptides are the first reported dynorphin A analogs containing a conformationally constrained amino acid in place of the important aromatic residue Phe4. By incorporating resolved Atc isomers, the opioid receptor affinity and the stereochemistry of the constrained residue could be unambiguously correlated. Both Dyn A analogs containing Atc in position 4 retained nanomolar affinity for kappa and mu opioid receptors. Unexpectedly the peptide containing (R)-Atc, corresponding to a conformationally constrained D-Phe analog, displaying higher affinity for both kappa and mu receptors than the peptide containing (S)-Atc. In contrast [D-Phe4,D-Ala8]Dyn A-(1-11)NH2 exhibited significantly lower affinity for kappa and mu receptors than the parent peptide, as expected. Conformational restriction of the Phe4 sidechain or incorporation of D-Phe in position 4 had the largest effect on delta receptor affinity, yielding compounds with negligible affinity for these receptors. Thus, there appear to be distinctly different structural requirements for this residue for kappa vs. delta receptors, and it is possible to completely distinguish between these two receptors by changing a single residue in Dyn A.
- Published
- 2001
28. Characterization of [3H]MK-801 binding to N-methyl-D-aspartate receptors in cultured rat cerebellar granule neurons and involvement in glutamate-mediated toxicity
- Author
-
Frederick W. Berman and Thomas F. Murray
- Subjects
education.field_of_study ,Cerebellum ,Chemistry ,Population ,Glutamate receptor ,Dextromethorphan ,Glutamic acid ,Pharmacology ,Toxicology ,Neuroprotection ,medicine.anatomical_structure ,nervous system ,Dextrorphan ,medicine ,Biophysics ,NMDA receptor ,education ,medicine.drug - Abstract
The conditions required for growth and survival of cerebellar granule neurons in vitro are known to alter the developmental regulation of NMDA receptor subunit mRNA. In the present report, we have examined the functional and pharmacological characteristics of NMDA receptors on cerebellar granule neurons at 12 days in culture (12 DIC). Under open-channel conditions in extensively washed membranes, [3H]MK-801 labeled a uniform population of sites (Kd = 3.2 +/- 0.3 nM) in a saturable manner (Bmax = 416 +/- 18 fmol/mg); however, biexponential association and dissociation kinetics indicated the possible existence of at least two NMDA receptor populations that differ in pharmacological properties. The kinetically derived equilibrium dissociation constants for the high- and low-affinity binding components were 0.56 and 771 nM, respectively. The equilibrium competition analysis of MK-801 and other channel-blocking compounds as displacers of [3H]MK-801 revealed the presence of high- and low-affinity binding sites with relative apportionments of 70% and 30%, respectively. The rank-order potency profile of competitor binding at the high-affinity site was (+)-MK-801 > TCP > dextrorphan > dextromethorphan > (+)-ketamine. When tested for the ability to protect 12 DIC cerebellar granule neurons from acute glutamate-induced toxicity, the neuroprotective rank-order potency of these compounds was MK-801 > TCP > dextrorphan > (+)-ketamine > dextromethorphan, which correlated significantly with the high-affinity competition binding profile and thus established the role of NMDA receptors in glutamate toxicity. The findings of these experiments indicate that NMDA receptors on 12 DIC cerebellar granule neurons are a heterogenous population that functionally mediate glutamate-induced neurotoxicity. The heterogenous [3H]MK-801 binding sites may represent NMDA receptor channels composed of different subunits.
- Published
- 1996
29. Characterization of glutamate toxicity in cultured rat cerebellar granule neurons at reduced temperature
- Author
-
Thomas F. Murray and Frederick W. Berman
- Subjects
Metabotropic glutamate receptor 5 ,Chemistry ,Excitotoxicity ,Kainate receptor ,AMPA receptor ,Pharmacology ,Toxicology ,medicine.disease_cause ,nervous system ,Biochemistry ,Metabotropic glutamate receptor ,medicine ,NMDA receptor ,Metabotropic glutamate receptor 1 ,Long-term depression - Abstract
We have defined conditions whereby glutamate becomes toxic to isolated cerebellar granule neurons in a physiologic salt solution (pH 7.4). In the presence of a physiologic Mg++ concentration, acute glutamate excitotoxicity manifests only when the temperature was reduced from 37°C to 22°C. In contrast to glutamate, N-methyl-D-aspartate (NMDA) was non-toxic at either temperature at concentrations as high as 1 mM. Glycine strongly potentiated both the potency and efficacy of glutamate but revealed only a modest NMDA response. The non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxalinedione (CNQX), potently protected against glutamate challenge, although the contribution of antagonism at strychnine-insensitive glycine sites could not be excluded. To further characterize the non-NMDA receptor contribution to the excitotoxic response, the promiscuity of glutamate interaction with ionotropic receptors was simulated by exposing neurons to NMDA in the presence of non-NMDA receptor agonists. NMDA toxicity was potentiated four- to sevenfold when non-NMDA receptors were coactivated by a subtoxic concentration of AMPA, kainate, or domoate. These results suggest that non-NMDA receptor activation participates in the mechanism of acute glutamate toxicity by producing neuronal depolarization (via sodium influx), which in turn promotes the release of the voltage-dependent magnesium blockade of NMDA receptor ion channels. © 1997 John Wiley & Sons, Inc.
- Published
- 1996
30. Sodium channel activator‐stimulated neuronal development involves BDNF‐TrkB signaling
- Author
-
Thomas F. Murray and Sairam V. Jabba
- Subjects
Activator (genetics) ,Chemistry ,Sodium channel ,Genetics ,Tropomyosin receptor kinase B ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2012
31. Sodium channel activator‐induced neurite outgrowth is NMDA receptor dependent and involves a TrkB‐PLCγ‐PI3K‐Akt pathway
- Author
-
Thomas F. Murray and Sairam V. Jabba
- Subjects
Neurite ,Activator (genetics) ,Chemistry ,Sodium channel ,Genetics ,NMDA receptor ,Tropomyosin receptor kinase B ,Molecular Biology ,Biochemistry ,PI3K/AKT/mTOR pathway ,Biotechnology ,Cell biology - Published
- 2011
32. Biphasic influence of sodium channel activation on neuronal structural plasticity
- Author
-
Thomas F. Murray and Joju George
- Subjects
Chemistry ,Sodium channel ,Structural plasticity ,Genetics ,Biophysics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2011
33. ChemInform Abstract: Palmyrolide A, an Unusually Stabilized Neuroactive Macrolide from Palmyra Atoll Cyanobacteria
- Author
-
Thomas F. Murray, Irma E. Soria-Mercado, Alban R. Pereira, Niclas Engene, Zhengyu Cao, and William H. Gerwick
- Subjects
Cyanobacteria ,biology ,Chemistry ,Palmyra Atoll ,Stereochemistry ,Absolute configuration ,General Medicine ,biology.organism_classification - Abstract
The absolute configuration is determined at C-14, whereas between C-5 and C-7 only a syn relative configuration can be established.
- Published
- 2011
34. Manipulation of endogenous adenosine affects seizure susceptibility
- Author
-
Paul H. Franklin, Thomas F. Murray, and Ge Zhang
- Subjects
medicine.medical_specialty ,Adenosine transport ,biology ,business.industry ,Dilazep ,Adenosine kinase ,Adenosine A3 receptor ,Adenosine ,Adenosine receptor ,Adenosine A1 receptor ,Endocrinology ,Internal medicine ,Drug Discovery ,Convulsion ,medicine ,biology.protein ,medicine.symptom ,business ,medicine.drug - Abstract
A1 adenosine receptors in rat prepiriform cortex (PPC) play an important role in the inhibition of bicuculline methiodide (BMI)-induced convulsions. In the present study, we evaluated the manipulation of endogenous adenosine in this brain area as a strategy to effect seizure suppression. All compounds evaluated were unilaterally microinjected into the PPC. Focal administration of 5′NH25′dADO and dilazep were found to be highly efficacious as anticonvulsants with respective ED50 values of 2.6±0.8, and 5.6±1.6 nmol. In contrast, 2′DCF was both less potent and less efficacious. These results suggest that accumulation of endogenous adenosine may contribute to seizure suppression, and that adenosine kinase and adenosine transport may play a pivotal role in the regulation of extracellular levels of adenosine in the CNS. © 1993 Wiley-Liss, Inc.
- Published
- 1993
35. Sodium channel activator‐induced neuronal development is NMDA receptor dependent and involves a Ca 2+ /calmodulin kinase (CaMK)‐CREB‐BDNF signaling pathway
- Author
-
Joju George and Thomas F. Murray
- Subjects
biology ,Activator (genetics) ,Chemistry ,Sodium channel ,CREB ,Biochemistry ,Cell biology ,Ca2+/calmodulin-dependent protein kinase ,Genetics ,biology.protein ,NMDA receptor ,Signal transduction ,Molecular Biology ,CAMK ,Biotechnology - Published
- 2010
36. Involvement of Phosphoinositide 3‐kinase‐Akt signaling pathway in sodium channel activator‐induced neurite outgrowth
- Author
-
Sairam V. Jabba, William H. Gerwick, and Thomas F. Murray
- Subjects
endocrine system diseases ,Neurite ,Chemistry ,Activator (genetics) ,Sodium channel ,Phosphoinositide 3 kinase akt ,nutritional and metabolic diseases ,Biochemistry ,Cell biology ,nervous system ,Synaptic plasticity ,Genetics ,NMDA receptor ,Signal transduction ,Receptor ,Molecular Biology ,hormones, hormone substitutes, and hormone antagonists ,Biotechnology - Abstract
Calcium influx through N-methyl D-aspartate receptors (NMDAR) regulates signaling cascades that underlie neuronal development and synaptic plasticity. Earlier we demonstrated that the voltage-gated...
- Published
- 2010
37. ChemInform Abstract: Alotamide A (I), a Novel Neuropharmacological Agent from the Marine Cyanobacterium Lyngbya bouillonii
- Author
-
Alban R. Pereira, Thomas F. Murray, Irma E. Soria-Mercado, William H. Gerwick, and Zhengyu Cao
- Subjects
Chemistry ,Stereochemistry ,Lyngbya bouillonii ,General Medicine - Published
- 2010
38. Pertussis Toxin in the A10 Region Increases Dopamine Synthesis and Metabolism
- Author
-
Thomas F. Murray, Peter W. Kalivas, Jeffery D. Steketee, and Caryn D. Striplin
- Subjects
Male ,medicine.medical_specialty ,Tyrosine 3-Monooxygenase ,G protein ,Dopamine ,Nucleus accumbens ,Biology ,Pertussis toxin ,Biochemistry ,Catalysis ,Nucleus Accumbens ,Cellular and Molecular Neuroscience ,Dopamine receptor D1 ,Mesencephalon ,Internal medicine ,medicine ,Animals ,Virulence Factors, Bordetella ,Red Nucleus ,Adenosine Diphosphate Ribose ,Rats, Inbred Strains ,Immunohistochemistry ,Potassium channel ,Rats ,Endocrinology ,Pertussis Toxin ,Dopamine receptor ,Autoreceptor ,Raphe Nuclei ,medicine.drug - Abstract
Inhibitory regulation of dopamine neurons is mediated by dopamine autoreceptor and gamma-aminobutyric acidB receptor opening of potassium channels. Increased potassium conductance by either receptor is G protein dependent. To evaluate the role of G proteins in vivo, pertussis toxin (PTX) was microinjected into the A10 dopamine region and changes in dopamine metabolism and synthesis measured. PTX produced an elevation in dopamine metabolism and synthesis in the A10 region and nucleus accumbens for up to 4 days after injection. By day 7 the levels of the dopamine precursor and metabolites had returned to normal. A less consistent increase was also measured in the A9 dopamine region and the prefrontal cortex. Although dopamine synthesis and metabolism had returned to normal by day 7, the in vitro ADP-ribosylation of G proteins in the A10 region by PTX remained depressed by approximately 50% from day 1 to day 14 after administration, returning to normal by day 30. The data suggest that in vivo ribosylation of G proteins may lead to a short-term attenuation of the tonic inhibitory control of dopamine neurons, which can be compensated for by PTX-insensitive mechanisms.
- Published
- 1992
39. Sodium channel activation modulates synchronized calcium oscillations and neuronal morphology in immature cerebrocortical neurons
- Author
-
Joju George and Thomas F. Murray
- Subjects
Morphology (linguistics) ,Chemistry ,Sodium channel ,Genetics ,Biophysics ,chemistry.chemical_element ,Calcium ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2009
40. ChemInform Abstract: Solid-Phase Synthesis and Application of Labeled Peptide Derivatives: Probes of Receptor-Opioid Peptide Interactions
- Author
-
Bhaswati Dattachowdhury, Angela M. Peck, Jane V. Aldrich, Vivek Kumar, Thomas F. Murray, and Xin Wang
- Subjects
chemistry.chemical_classification ,biology ,Stereochemistry ,Affinity label ,Peptide ,General Medicine ,chemistry.chemical_compound ,Solid-phase synthesis ,chemistry ,Biotin ,Opioid ,Isothiocyanate ,medicine ,biology.protein ,Opioid peptide ,Receptor ,medicine.drug - Abstract
Solid phase synthetic methodology has been developed in our laboratory to incorporate an affinity label (a reactive functionality such as isothiocyanate or bromoacetamide) into peptides (Leelasvatanakij and Aldrich J Peptide Res 56, 80, 2000), and we have used this synthetic strategy to prepare affinity label derivatives of a variety of opioid peptides. To date side reactions have been detected only in two cases, both involving intramolecular cyclization. We have identified several peptide-based affinity labels for δ opioid receptors that exhibit wash-resistant inhibition of binding to these receptors and are valuable pharmacological tools to study opioid receptors. Even in cases where the peptide derivatives do not bind covalently to their target receptor, studying their binding has revealed subtle differences in receptor interactions with particular opioid peptide residues, especially Phe residues in the N-terminal “message” sequences. Solid phase synthetic methodology for the incorporation of other labels (e.g. biotin) into the C-terminus of peptides has also been developed in our laboratory (Kumar and Aldrich Org Lett 5, 613, 2003). These two synthetic approaches have been combined to prepare peptides containing multiple labels that can be used as tools to study peptide ligand-receptor interactions. These solid phase synthetic methodologies are versatile strategies that are applicable to the preparation of labeled peptides for a variety of targets in addition to opioid receptors.
- Published
- 2009
41. Brevetoxin sensitizes immature cerebrocortical neurons to NMDA receptor signaling through activation of voltage‐gated sodium channels
- Author
-
Thomas F. Murray, Joju George, and Zhengyu Cao
- Subjects
Brevetoxin ,Chemistry ,Sodium channel ,Genetics ,Biophysics ,NMDA receptor ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2008
42. Brevetoxin enhanced neurite growth involves voltage‐gated sodium channel activation with engagement of NMDA receptors and CaM‐kinase kinase
- Author
-
Jun Xie, Jennifer M. Peterson, and Thomas F. Murray
- Subjects
Brevetoxin ,Neurite growth ,Biochemistry ,Kinase ,Chemistry ,Ca2+/calmodulin-dependent protein kinase ,Sodium channel ,Genetics ,NMDA receptor ,Molecular Biology ,Biotechnology ,Cell biology - Published
- 2007
43. Characterization of Muscarinic Cholinergic Receptors in the Crab Nervous System
- Author
-
Joseph F. Siebenaller, George J. Mpitsos, David L. Barker, and Thomas F. Murray
- Subjects
Male ,medicine.medical_specialty ,Carbachol ,Brachyura ,Decamethonium Compounds ,Arecoline ,Tubocurarine ,Biology ,Binding, Competitive ,Nervous System ,Biochemistry ,Cellular and Molecular Neuroscience ,Internal medicine ,Muscarinic acetylcholine receptor ,medicine ,Oxotremorine ,Animals ,Tissue Distribution ,Nervous tissue ,Pilocarpine ,Muscarinic antagonist ,Stereoisomerism ,Receptors, Muscarinic ,Quinuclidinyl Benzilate ,Kinetics ,Endocrinology ,medicine.anatomical_structure ,Mathematics ,medicine.drug - Abstract
The selective muscarinic antagonist L-[3H]-quinuclidinyl benzilate (L-[3H]QNB) binds reversibly and with high affinity (KD= 0.3 nM) to a single population (Bmax= 105 fmol/mg protein) of specific sites in nervous tissue of the crab Cancer magister. The binding site is stereoselective; (-)QNB is over 200 times more potent than (+)QNB as an inhibitor of specific L-[3H]QNB binding. The muscarinic antagonists scopolamine and atropine are over 10,000 times more potent inhibitors of L-[3H]QNB binding than the nicotinic antagonists deca-methonium and d-tubocurarine. The muscarinic agonists oxotremorine, pilocarpine, arecoline, and carbachol also compete effectively for the L-[3H]QNB binding site. This pharmacological profile strongly suggests the presence of classical muscarinic receptors in the crab nervous system. These receptors are localized to nervous tissue containing cell bodies and neuropil, whereas specific L-[3H]QNB binding is low or absent in peripheral nerve, skeletal muscle, and artery.
- Published
- 1986
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