Olga Grigoriants - Academia.edu (original) (raw)

Papers by Olga Grigoriants

Journal of Pharmacology and Experimental Therapeutics, 1998

Although synthetic opioid peptide analogs have been used extensively to study the functional role... more Although synthetic opioid peptide analogs have been used extensively to study the functional roles of opioid receptors, little is known about their in vivo disposition. Our goal was to develop novel opioid drugs with limited transfer across the placenta. DALDA (Tyr-D-Arg-Phe-Lys-NH2) is a potent and highly selective mu agonist that is quite polar because of its 3+ charge at physiological pH. It can therefore be expected that the distribution of DALDA across the placenta would be highly restricted. In this study, we determined the pharmacokinetics and placental transfer of DALDA after systemic administration in sheep. DALDA was infused intravenously to four nonpregnant and four pregnant sheep at a dose of 0.6 mg/kg/hr for 4 hr. Steady state plasma levels of DALDA were 5436 +/- 464 ng/ml in nonpregnant sheep and 5214 +/- 661 ng/ml in pregnant sheep. A one-compartment open model provided an excellent fit for nonpregnant and pregnant plasma data. The apparent volume of distribution was estimated to be 45.6 +/- 4.4 and 59.2 +/- 7.9 ml/kg in nonpregnant and pregnant animals, respectively. There was no difference in the elimination half-life of DALDA in nonpregnant (1.4 +/- 0.1 hr) and pregnant (1.7 +/- 0.2 hr) animals, and clearance was also similar in nonpregnant (23.1 +/- 1.7 ml/kg/hr) and pregnant (23.7 +/- 1.3 ml/kg/hr) animals. These data suggest that the distribution of DALDA is restricted to plasma volume and that its disposition is not altered in pregnancy. DALDA was not detected in any of the fetal plasma samples (< 50 ng/ml), indicating that fetal plasma concentration is < 1% of maternal concentration. The highly restricted placental distribution of DALDA suggests that it may be a promising opioid drug for obstetrical use.

respectively. 1 Copyright © 2006 by the American Physiological Society. Page 2 of 38 Although chr... more respectively. 1 Copyright © 2006 by the American Physiological Society. Page 2 of 38 Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, DAMGO and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: (1) Chronic treatment with morphine for> 3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, “internalizing ” opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. (2) MOR-GFP is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal non-spiny n...

European Journal of Cancer Supplements, 2004

The Journal of pharmacology and experimental therapeutics, 1998

Although synthetic opioid peptide analogs have been used extensively to study the functional role... more Although synthetic opioid peptide analogs have been used extensively to study the functional roles of opioid receptors, little is known about their in vivo disposition. Our goal was to develop novel opioid drugs with limited transfer across the placenta. DALDA (Tyr-D-Arg-Phe-Lys-NH2) is a potent and highly selective mu agonist that is quite polar because of its 3+ charge at physiological pH. It can therefore be expected that the distribution of DALDA across the placenta would be highly restricted. In this study, we determined the pharmacokinetics and placental transfer of DALDA after systemic administration in sheep. DALDA was infused intravenously to four nonpregnant and four pregnant sheep at a dose of 0.6 mg/kg/hr for 4 hr. Steady state plasma levels of DALDA were 5436 +/- 464 ng/ml in nonpregnant sheep and 5214 +/- 661 ng/ml in pregnant sheep. A one-compartment open model provided an excellent fit for nonpregnant and pregnant plasma data. The apparent volume of distribution was ...

Molecular Brain Research, 1993

International journal of peptide and protein research

Mass spectrometry was used to determine the molecular mass of rat pituitary beta-endorphin1-31 (B... more Mass spectrometry was used to determine the molecular mass of rat pituitary beta-endorphin1-31 (BErat, 1-31). The measured molecular mass (3435 +/- 1 Da, n = 5) of endogenous BErat, 1-31 differed from the molecular mass of commercially available synthetic BErat, 1-31 (3465 +/- 1 Da, n = 9), but corresponded to the molecular mass of synthetic BEbovine, 1-31 (3436 +/- 3 Da, n = 3). Based on the combination of these ESIMS molecular mass measurements, HPLC retention time data, LSIMS measurement of the molecular mass of selected tryptic fragments, and consideration of codon sequences, we suggest that the amino-acid sequence of endogenous BErat, 1-31 differs from the DNA-deduced sequence of BErat, 1-31, and that endogenous BErat, 1-31 contains Ala instead of Val in position 26.

International Journal of Peptide and Protein Research, 2009

Primed 811 Belgrwnall righrs reserved Cop~right 0 Munkrpord I996 INTERNATIONAL lOVRN.4L OF PEPTIDE.

Neurochemical Research, 1995

Concentration changes of methionine enkephalin-like immunoreactivity (ME-li) and beta-endorphin-l... more Concentration changes of methionine enkephalin-like immunoreactivity (ME-li) and beta-endorphin-like immunoreactivity (BE-li) in the rat pituitary following diffuse brain injury were studied. Closed head injury was induced by a weight-drop trauma device (450 g x 2 m). The level of closed head injury used in this study altered the pituitary opioid peptide concentrations. The level of ME-li did not change in the experimental groups 3 hours, 10 hours, 24 hours, and 3 days after the trauma, but significantly increased by 34% 10 days after the trauma. BE-li remained constant 3 hours and 10 hours following the injury, increased by 48% at 24 hours, and remained at this level for 10 days after the trauma (44% at 3 days, and 40% at 10 days). The levels of ME-li and BE-li in the control sham-operated rats did not change during these times. The present measurements of BE-li and ME-li in the pituitary indicate that the opioid peptides that derive from two different neuropeptidergic systems, proopiomelanocortin (POMC) and preproenkephalin A, respectively, may participate in the pathophysiology of a closed head injury.

Letters in Drug Design & Discovery, 2007

ABSTRACT Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-... more ABSTRACT Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two α -methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized and evaluated for their anti-cancer activity. Preliminary screening indicated that the (S)- isomers displayed improved activity in comparison with (R)- enantiomers to inhibit tubulin polymerization and activate caspase- 3. In accordance with these results, the thiourea derivatives displayed potent anti-cancer activity against human B-lineage (Nalm-6) and T-lineage (Molt-3) acute lymphoblastic leukemia cell lines. Based on the results we conclude that the anti-leukemic activity of these compounds also depends on their chirality.

International Journal of Peptide and Protein Research, 2009

Mass spectrometry was used to determine the molecular mass of rat pituitary β-endorphin1–31 (BEra... more Mass spectrometry was used to determine the molecular mass of rat pituitary β-endorphin1–31 (BErat, 1–31 The measured molecular mass (3435 ± 1 Da, n= 5) of endogenous BErat, 1–31 differed from the molecular mass of commercially available synthetic BErat, 1–31 (3465 ± 1 Da, n= 9), but corresponded to the molecular mass of synthetic BEbovine, 1–31 (3436 ± 3 Da, n= 3). Based on the combination of these ESIMS molecular mass measurements, HPLC retention time data, LSIMS measurement of the molecular mass of selected tryptic fragments, and consideration of codon sequences, we suggest that the amino-acid sequence of endogenous BErat, 1–31differs from the DNA-deduced sequence of BErat, 1–31, and that endogenous BErat, 1–31 contains Ala instead of Val in position 26. ©Munksgaard 1996.

Cheminform, 2005

For Abstract see ChemInform Abstract in Full Text.

Journal of Neurophysiology, 2006

Although chronic treatment with morphine is known to alter the function and morphology of excitat... more Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, [d-ala(2),me-phe(4),gly(5)-ol]enkephalin (DAMGO), and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: 1) chronic treatment with morphine for >3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, "internalizing" opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. 2) mu opioid receptor fused with green fluorescence protein (MOR-GFP) is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal nonspiny neurons. It suggests that MORs might mediate pre- or postsynaptic effects depending on cell types. 3) Neurons were cultured from MOR knock-out mice and were exogenously transfected with MOR-GFP. Chronic treatment with morphine suppressed mEPSCs only in neurons that contained postsynaptic MOR-GFP, indicating that opioids can modulate excitatory synaptic transmission postsynaptically. 4) Morphine acutely decreased mEPSC amplitude in neurons expressing exogenous MOR-GFP but had no effect on neurons expressing GFP. It indicates that the low level of endogenous MORs could only allow slow opioid-induced plasticity of excitatory synapses under normal conditions. 5) A theoretical model suggests that morphine might affect the function of spines by decreasing the electrotonic distance from synaptic inputs to the soma.

Journal of Chromatography B: Biomedical Sciences and Applications, 1997

The mu opioid receptor agonist Tyr-D-Arg-Phe-Lys-Amide (D-Arg2-Lys4-Dermorphin(1-4)amide=DALDA) w... more The mu opioid receptor agonist Tyr-D-Arg-Phe-Lys-Amide (D-Arg2-Lys4-Dermorphin(1-4)amide=DALDA) was infused continuously for 2 h into sheep. The presence of DALDA in ovine plasma was determined by reversed-phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry (MS) in plasma samples that were obtained at different times during and following that infusion. A stable isotope-incorporated internal standard, deuterated DALDA (d5-DALDA), was used for the MS quantification of DALDA via the protonated molecule ion, (M+H)+, of DALDA and of d5-DALDA. Time-course data (microg DALDA ml(-1) plasma vs. time) were obtained. Tandem MS (MS-MS) provided the product-ion spectrum of the (M+H)+ ion of DALDA in one of the samples to confirm the amino acid sequence of DALDA.

Molecular and Cellular Neuroscience, 2007

This study has examined the relationship between the effects of opioids on the internalization of... more This study has examined the relationship between the effects of opioids on the internalization of mu opioid receptors (MORs) and the morphology of dendritic spines. Several opioids (morphine, etorphine, DAMGO or methadone) were applied to cultured hippocampal neurons. Live imaging and biochemical techniques were used to examine the dynamic changes in MOR internalization and spine morphology. This study reveals that MOR internalization can regulate opioid-induced morphological changes in dendritic spines: (1) Chronic treatment with morphine, which induced minimal receptor internalization, caused collapse of dendritic spines. In contrast, "internalizing" opioids such as DAMGO and etorphine induced the emergence of new spines. It reveals that opioid-induced changes in spines vary greatly depending on how the applied opioid agonist affects MOR internalization.

Journal of Pharmacology and Experimental Therapeutics, 1998

Although synthetic opioid peptide analogs have been used extensively to study the functional role... more Although synthetic opioid peptide analogs have been used extensively to study the functional roles of opioid receptors, little is known about their in vivo disposition. Our goal was to develop novel opioid drugs with limited transfer across the placenta. DALDA (Tyr-D-Arg-Phe-Lys-NH2) is a potent and highly selective mu agonist that is quite polar because of its 3+ charge at physiological pH. It can therefore be expected that the distribution of DALDA across the placenta would be highly restricted. In this study, we determined the pharmacokinetics and placental transfer of DALDA after systemic administration in sheep. DALDA was infused intravenously to four nonpregnant and four pregnant sheep at a dose of 0.6 mg/kg/hr for 4 hr. Steady state plasma levels of DALDA were 5436 +/- 464 ng/ml in nonpregnant sheep and 5214 +/- 661 ng/ml in pregnant sheep. A one-compartment open model provided an excellent fit for nonpregnant and pregnant plasma data. The apparent volume of distribution was estimated to be 45.6 +/- 4.4 and 59.2 +/- 7.9 ml/kg in nonpregnant and pregnant animals, respectively. There was no difference in the elimination half-life of DALDA in nonpregnant (1.4 +/- 0.1 hr) and pregnant (1.7 +/- 0.2 hr) animals, and clearance was also similar in nonpregnant (23.1 +/- 1.7 ml/kg/hr) and pregnant (23.7 +/- 1.3 ml/kg/hr) animals. These data suggest that the distribution of DALDA is restricted to plasma volume and that its disposition is not altered in pregnancy. DALDA was not detected in any of the fetal plasma samples (< 50 ng/ml), indicating that fetal plasma concentration is < 1% of maternal concentration. The highly restricted placental distribution of DALDA suggests that it may be a promising opioid drug for obstetrical use.

respectively. 1 Copyright © 2006 by the American Physiological Society. Page 2 of 38 Although chr... more respectively. 1 Copyright © 2006 by the American Physiological Society. Page 2 of 38 Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, DAMGO and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: (1) Chronic treatment with morphine for> 3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, “internalizing ” opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. (2) MOR-GFP is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal non-spiny n...

European Journal of Cancer Supplements, 2004

The Journal of pharmacology and experimental therapeutics, 1998

Although synthetic opioid peptide analogs have been used extensively to study the functional role... more Although synthetic opioid peptide analogs have been used extensively to study the functional roles of opioid receptors, little is known about their in vivo disposition. Our goal was to develop novel opioid drugs with limited transfer across the placenta. DALDA (Tyr-D-Arg-Phe-Lys-NH2) is a potent and highly selective mu agonist that is quite polar because of its 3+ charge at physiological pH. It can therefore be expected that the distribution of DALDA across the placenta would be highly restricted. In this study, we determined the pharmacokinetics and placental transfer of DALDA after systemic administration in sheep. DALDA was infused intravenously to four nonpregnant and four pregnant sheep at a dose of 0.6 mg/kg/hr for 4 hr. Steady state plasma levels of DALDA were 5436 +/- 464 ng/ml in nonpregnant sheep and 5214 +/- 661 ng/ml in pregnant sheep. A one-compartment open model provided an excellent fit for nonpregnant and pregnant plasma data. The apparent volume of distribution was ...

Molecular Brain Research, 1993

International journal of peptide and protein research

Mass spectrometry was used to determine the molecular mass of rat pituitary beta-endorphin1-31 (B... more Mass spectrometry was used to determine the molecular mass of rat pituitary beta-endorphin1-31 (BErat, 1-31). The measured molecular mass (3435 +/- 1 Da, n = 5) of endogenous BErat, 1-31 differed from the molecular mass of commercially available synthetic BErat, 1-31 (3465 +/- 1 Da, n = 9), but corresponded to the molecular mass of synthetic BEbovine, 1-31 (3436 +/- 3 Da, n = 3). Based on the combination of these ESIMS molecular mass measurements, HPLC retention time data, LSIMS measurement of the molecular mass of selected tryptic fragments, and consideration of codon sequences, we suggest that the amino-acid sequence of endogenous BErat, 1-31 differs from the DNA-deduced sequence of BErat, 1-31, and that endogenous BErat, 1-31 contains Ala instead of Val in position 26.

International Journal of Peptide and Protein Research, 2009

Primed 811 Belgrwnall righrs reserved Cop~right 0 Munkrpord I996 INTERNATIONAL lOVRN.4L OF PEPTIDE.

Neurochemical Research, 1995

Concentration changes of methionine enkephalin-like immunoreactivity (ME-li) and beta-endorphin-l... more Concentration changes of methionine enkephalin-like immunoreactivity (ME-li) and beta-endorphin-like immunoreactivity (BE-li) in the rat pituitary following diffuse brain injury were studied. Closed head injury was induced by a weight-drop trauma device (450 g x 2 m). The level of closed head injury used in this study altered the pituitary opioid peptide concentrations. The level of ME-li did not change in the experimental groups 3 hours, 10 hours, 24 hours, and 3 days after the trauma, but significantly increased by 34% 10 days after the trauma. BE-li remained constant 3 hours and 10 hours following the injury, increased by 48% at 24 hours, and remained at this level for 10 days after the trauma (44% at 3 days, and 40% at 10 days). The levels of ME-li and BE-li in the control sham-operated rats did not change during these times. The present measurements of BE-li and ME-li in the pituitary indicate that the opioid peptides that derive from two different neuropeptidergic systems, proopiomelanocortin (POMC) and preproenkephalin A, respectively, may participate in the pathophysiology of a closed head injury.

Letters in Drug Design & Discovery, 2007

ABSTRACT Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-... more ABSTRACT Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two α -methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized and evaluated for their anti-cancer activity. Preliminary screening indicated that the (S)- isomers displayed improved activity in comparison with (R)- enantiomers to inhibit tubulin polymerization and activate caspase- 3. In accordance with these results, the thiourea derivatives displayed potent anti-cancer activity against human B-lineage (Nalm-6) and T-lineage (Molt-3) acute lymphoblastic leukemia cell lines. Based on the results we conclude that the anti-leukemic activity of these compounds also depends on their chirality.

International Journal of Peptide and Protein Research, 2009

Mass spectrometry was used to determine the molecular mass of rat pituitary β-endorphin1–31 (BEra... more Mass spectrometry was used to determine the molecular mass of rat pituitary β-endorphin1–31 (BErat, 1–31 The measured molecular mass (3435 ± 1 Da, n= 5) of endogenous BErat, 1–31 differed from the molecular mass of commercially available synthetic BErat, 1–31 (3465 ± 1 Da, n= 9), but corresponded to the molecular mass of synthetic BEbovine, 1–31 (3436 ± 3 Da, n= 3). Based on the combination of these ESIMS molecular mass measurements, HPLC retention time data, LSIMS measurement of the molecular mass of selected tryptic fragments, and consideration of codon sequences, we suggest that the amino-acid sequence of endogenous BErat, 1–31differs from the DNA-deduced sequence of BErat, 1–31, and that endogenous BErat, 1–31 contains Ala instead of Val in position 26. ©Munksgaard 1996.

Cheminform, 2005

For Abstract see ChemInform Abstract in Full Text.

Journal of Neurophysiology, 2006

Although chronic treatment with morphine is known to alter the function and morphology of excitat... more Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, [d-ala(2),me-phe(4),gly(5)-ol]enkephalin (DAMGO), and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: 1) chronic treatment with morphine for >3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, "internalizing" opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. 2) mu opioid receptor fused with green fluorescence protein (MOR-GFP) is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal nonspiny neurons. It suggests that MORs might mediate pre- or postsynaptic effects depending on cell types. 3) Neurons were cultured from MOR knock-out mice and were exogenously transfected with MOR-GFP. Chronic treatment with morphine suppressed mEPSCs only in neurons that contained postsynaptic MOR-GFP, indicating that opioids can modulate excitatory synaptic transmission postsynaptically. 4) Morphine acutely decreased mEPSC amplitude in neurons expressing exogenous MOR-GFP but had no effect on neurons expressing GFP. It indicates that the low level of endogenous MORs could only allow slow opioid-induced plasticity of excitatory synapses under normal conditions. 5) A theoretical model suggests that morphine might affect the function of spines by decreasing the electrotonic distance from synaptic inputs to the soma.

Journal of Chromatography B: Biomedical Sciences and Applications, 1997

The mu opioid receptor agonist Tyr-D-Arg-Phe-Lys-Amide (D-Arg2-Lys4-Dermorphin(1-4)amide=DALDA) w... more The mu opioid receptor agonist Tyr-D-Arg-Phe-Lys-Amide (D-Arg2-Lys4-Dermorphin(1-4)amide=DALDA) was infused continuously for 2 h into sheep. The presence of DALDA in ovine plasma was determined by reversed-phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry (MS) in plasma samples that were obtained at different times during and following that infusion. A stable isotope-incorporated internal standard, deuterated DALDA (d5-DALDA), was used for the MS quantification of DALDA via the protonated molecule ion, (M+H)+, of DALDA and of d5-DALDA. Time-course data (microg DALDA ml(-1) plasma vs. time) were obtained. Tandem MS (MS-MS) provided the product-ion spectrum of the (M+H)+ ion of DALDA in one of the samples to confirm the amino acid sequence of DALDA.

Molecular and Cellular Neuroscience, 2007

This study has examined the relationship between the effects of opioids on the internalization of... more This study has examined the relationship between the effects of opioids on the internalization of mu opioid receptors (MORs) and the morphology of dendritic spines. Several opioids (morphine, etorphine, DAMGO or methadone) were applied to cultured hippocampal neurons. Live imaging and biochemical techniques were used to examine the dynamic changes in MOR internalization and spine morphology. This study reveals that MOR internalization can regulate opioid-induced morphological changes in dendritic spines: (1) Chronic treatment with morphine, which induced minimal receptor internalization, caused collapse of dendritic spines. In contrast, "internalizing" opioids such as DAMGO and etorphine induced the emergence of new spines. It reveals that opioid-induced changes in spines vary greatly depending on how the applied opioid agonist affects MOR internalization.