The Experts below are selected from a list of 75735 Experts worldwide ranked by ideXlab platform
Henry I Mosberg - One of the best experts on this subject based on the ideXlab platform.
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further optimization and evaluation of bioavailable mixed efficacy μ opioid receptor Mor agonists δ opioid receptor dor antagonists balancing Mor and dor affinities
Journal of Medicinal Chemistry, 2015Co-Authors: Aubrie A Harland, Larisa Yeomans, Jessica P Anand, Emily M Jutkiewicz, John R Traynor, Nicholas W Griggs, Irina D Pogozheva, Henry I MosbergAbstract:In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (Mor) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between Mor and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired Mor agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.
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opioid peptidomimetics leads for the design of bioavailable mixed efficacy μ opioid receptor Mor agonist δ opioid receptor dor antagonist ligands
Journal of Medicinal Chemistry, 2013Co-Authors: Henry I Mosberg, Larisa Yeomans, Aubrie A Harland, Aaron M Bender, Katarzyna Sobczykkojiro, Jessica P Anand, Mary J Clark, Emily M Jutkiewicz, John R TraynorAbstract:We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a μ opioid receptor (Mor) agonist, δ opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of Mor agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood–brain barrier. Here we describe the transfer of structural features that evoked Mor agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to Morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid...
John R Traynor - One of the best experts on this subject based on the ideXlab platform.
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further optimization and evaluation of bioavailable mixed efficacy μ opioid receptor Mor agonists δ opioid receptor dor antagonists balancing Mor and dor affinities
Journal of Medicinal Chemistry, 2015Co-Authors: Aubrie A Harland, Larisa Yeomans, Jessica P Anand, Emily M Jutkiewicz, John R Traynor, Nicholas W Griggs, Irina D Pogozheva, Henry I MosbergAbstract:In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (Mor) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between Mor and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired Mor agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.
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opioid peptidomimetics leads for the design of bioavailable mixed efficacy μ opioid receptor Mor agonist δ opioid receptor dor antagonist ligands
Journal of Medicinal Chemistry, 2013Co-Authors: Henry I Mosberg, Larisa Yeomans, Aubrie A Harland, Aaron M Bender, Katarzyna Sobczykkojiro, Jessica P Anand, Mary J Clark, Emily M Jutkiewicz, John R TraynorAbstract:We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a μ opioid receptor (Mor) agonist, δ opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of Mor agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood–brain barrier. Here we describe the transfer of structural features that evoked Mor agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to Morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid...
Aubrie A Harland - One of the best experts on this subject based on the ideXlab platform.
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further optimization and evaluation of bioavailable mixed efficacy μ opioid receptor Mor agonists δ opioid receptor dor antagonists balancing Mor and dor affinities
Journal of Medicinal Chemistry, 2015Co-Authors: Aubrie A Harland, Larisa Yeomans, Jessica P Anand, Emily M Jutkiewicz, John R Traynor, Nicholas W Griggs, Irina D Pogozheva, Henry I MosbergAbstract:In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (Mor) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between Mor and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired Mor agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.
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opioid peptidomimetics leads for the design of bioavailable mixed efficacy μ opioid receptor Mor agonist δ opioid receptor dor antagonist ligands
Journal of Medicinal Chemistry, 2013Co-Authors: Henry I Mosberg, Larisa Yeomans, Aubrie A Harland, Aaron M Bender, Katarzyna Sobczykkojiro, Jessica P Anand, Mary J Clark, Emily M Jutkiewicz, John R TraynorAbstract:We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a μ opioid receptor (Mor) agonist, δ opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of Mor agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood–brain barrier. Here we describe the transfer of structural features that evoked Mor agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to Morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid...
A. Kluczyk - One of the best experts on this subject based on the ideXlab platform.
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synthesis of mixed Mor kor efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration
European Journal of Medicinal Chemistry, 2016Co-Authors: R. Perlikowska, J. Piekielna, M.c. Cerlesi, A. Kluczyk, Luca Gentilucci, Roberto Artali, Girolamo Calo, Rossella De Marco, Csaba Tomboly, Anna JaneckaAbstract:Abstract Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endoMorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (Mor) and a very strong antinociceptive activity in mice was used as a parent compound for the structure–activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the More extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar Mor and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs.
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Synthesis of mixed Mor/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration
European Journal of Medicinal Chemistry, 2016Co-Authors: R. Perlikowska, Carlos Ay??n, J. Piekielna, Riboldi Marco, M.c. Cerlesi, Luca Gentilucci, Roberto Artali, Girolamo Calo, A. KluczykAbstract:? 2015 Published by Elsevier Masson SAS.Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endoMorphin-2 (EM-2), which shows high affinity to the ?-opioid receptor (Mor) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the More extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar Mor and nanomolar ?-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs.
R. Perlikowska - One of the best experts on this subject based on the ideXlab platform.
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synthesis of mixed Mor kor efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration
European Journal of Medicinal Chemistry, 2016Co-Authors: R. Perlikowska, J. Piekielna, M.c. Cerlesi, A. Kluczyk, Luca Gentilucci, Roberto Artali, Girolamo Calo, Rossella De Marco, Csaba Tomboly, Anna JaneckaAbstract:Abstract Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endoMorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (Mor) and a very strong antinociceptive activity in mice was used as a parent compound for the structure–activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the More extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar Mor and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs.
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Synthesis of mixed Mor/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration
European Journal of Medicinal Chemistry, 2016Co-Authors: R. Perlikowska, Carlos Ay??n, J. Piekielna, Riboldi Marco, M.c. Cerlesi, Luca Gentilucci, Roberto Artali, Girolamo Calo, A. KluczykAbstract:? 2015 Published by Elsevier Masson SAS.Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endoMorphin-2 (EM-2), which shows high affinity to the ?-opioid receptor (Mor) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the More extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar Mor and nanomolar ?-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs.