Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide
Identifieur interne : 003831 ( Main/Exploration ); précédent : 003830; suivant : 003832Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide
Auteurs : E. M. Khalil [États-Unis] ; W. H. Ojala [États-Unis] ; A. Pradhan [Canada] ; V. D. Nair [Canada] ; W. B. Gleason [États-Unis] ; R. K. Mishra [Canada] ; R. L. Johnson [États-Unis]Source :
- Journal of medicinal chemistry [ 0022-2623 ] ; 1999.
Descripteurs français
- Pascal (Inist)
- Relation structure activité, Synthèse chimique, Hétérocycle soufre azote, Composé tricyclique, Spirane, Lactame, Carboxamide, Composé peptidomimétique, Composé non peptide, Rigidité moléculaire, Modélisation, Modèle moléculaire, Modulation, Fixation biologique, Affinité, Ligand, Récepteur dopaminergique D2, In vitro, In vivo, Rat, Animal, Voie intrapéritonéale, Antiparkinsonien, Pathologie expérimentale, Chimiothérapie, Traitement, Parkinson maladie, Spiro[pyrrolidine-2:7'-pyrrolo[2,1-b]thiazine-4'-carboxylique acide] dérivé, Spiro[pyrrolidine-2:6'-thiazolidino[3,2-a]pipéridine-3'carboxylique acide] dérivé.
English descriptors
- KwdEn :
- Affinity, Animal, Antiparkinson agent, Biological fixation, Carboxamide, Chemical synthesis, Chemotherapy, D2 Dopamine receptor, Experimental disease, In vitro, In vivo, Intraperitoneal administration, Lactam, Ligand, Modeling, Modulation, Molecular model, Molecular rigidity, Non peptide compound, Parkinson disease, Peptidomimetic compound, Rat, Spiran, Structure activity relation, Sulfur nitrogen heterocycle, Treatment, Tricyclic compound.
Abstract
In the present study, the synthesis of the 5.5.6. and 5.6.5. spiro bicyclic lactam PLG peptidomimetics, compounds 3 and 4, respectively, was undertaken. These peptidomimetics were designed to examine the following: (1) the effect that changing the size of the thiazolidine and lactam ring systems would have on the ability of these systems to mimic the type-II β-turn and (2) the effect that these structural perturbations would have on the ability of the peptidomimetics to modulate dopamine receptors. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) dopamine D2 receptor competitive binding assay, 3 and 4, at a concentration of 100 nM, decreased the dissociation constant of the high-affinity state of the dopamine receptor for the agonist. These effects were observed when either Gpp(NH)p was absent or present and they were comparable to those produced by PLG at a concentration of 1 μM. Peptidomimetics 3 and 4 also increased the percentage of D2 receptors that existed in the high-affinity state. Even with Gpp(NH)p present, 3 and 4 were able to return the RH/RL ratios to values observed in the respective controls where Gpp(NH)p was absent. Furthermore, both peptidomimetics were able to attenuate the Gpp(NH)p-induced shift to the low-affinity state to a greater extent than PLG. Peptidomimetics 3 and 4 were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism, and each affected the rotational behavior in a bell-shaped dose-response relationship producing increases of 95 ± 31% (0.01 mg/kg, ip) and 88 ± 14% (0.001 mg/kg, ip), respectively. In comparison, the previously reported 5.5.5. spiro bicyclic lactam 2 increased rotational behavior by 25 ± 11% (0.01 mg/kg, ip).
Affiliations:
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Gleason</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Biomedical Engineering Center and Department of Laboratory Medicine and Pathology, University of Minnesota</s1><s2>Minneapolis, Minnesota 55455</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Minneapolis, Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Mishra, R K" sort="Mishra, R K" uniqKey="Mishra R" first="R. K." last="Mishra">R. K. Mishra</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Psychiatry and Behavioural Neuroscience, McMaster University</s1><s2>Hamilton, Ontario L8N 3Z5</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université McMaster</orgName></affiliation></author><author><name sortKey="Johnson, R L" sort="Johnson, R L" uniqKey="Johnson R" first="R. L." last="Johnson">R. L. Johnson</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Medicinal Chemistry, University of Minnesota</s1><s2>Minneapolis, Minnesota 55455</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Minneapolis, Minnesota 55455</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">99-0217073</idno><date when="1999">1999</date><idno type="stanalyst">PASCAL 99-0217073 INIST</idno><idno type="RBID">Pascal:99-0217073</idno><idno type="wicri:Area/PascalFrancis/Corpus">000D73</idno><idno type="wicri:Area/PascalFrancis/Curation">001150</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000C64</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000C64</idno><idno type="wicri:doubleKey">0022-2623:1999:Khalil E:design:synthesis:and</idno><idno type="wicri:Area/Main/Merge">003E17</idno><idno type="wicri:Area/Main/Curation">003831</idno><idno type="wicri:Area/Main/Exploration">003831</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide</title><author><name sortKey="Khalil, E M" sort="Khalil, E M" uniqKey="Khalil E" first="E. M." last="Khalil">E. M. Khalil</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Medicinal Chemistry, University of Minnesota</s1><s2>Minneapolis, Minnesota 55455</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Minneapolis, Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Ojala, W H" sort="Ojala, W H" uniqKey="Ojala W" first="W. H." last="Ojala">W. H. Ojala</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Biomedical Engineering Center and Department of Laboratory Medicine and Pathology, University of Minnesota</s1><s2>Minneapolis, Minnesota 55455</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Minneapolis, Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Pradhan, A" sort="Pradhan, A" uniqKey="Pradhan A" first="A." last="Pradhan">A. Pradhan</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Psychiatry and Behavioural Neuroscience, McMaster University</s1><s2>Hamilton, Ontario L8N 3Z5</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université McMaster</orgName></affiliation></author><author><name sortKey="Nair, V D" sort="Nair, V D" uniqKey="Nair V" first="V. D." last="Nair">V. D. Nair</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Psychiatry and Behavioural Neuroscience, McMaster University</s1><s2>Hamilton, Ontario L8N 3Z5</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université McMaster</orgName></affiliation></author><author><name sortKey="Gleason, W B" sort="Gleason, W B" uniqKey="Gleason W" first="W. B." last="Gleason">W. B. Gleason</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>The Biomedical Engineering Center and Department of Laboratory Medicine and Pathology, University of Minnesota</s1><s2>Minneapolis, Minnesota 55455</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Minneapolis, Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Mishra, R K" sort="Mishra, R K" uniqKey="Mishra R" first="R. K." last="Mishra">R. K. Mishra</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Psychiatry and Behavioural Neuroscience, McMaster University</s1><s2>Hamilton, Ontario L8N 3Z5</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université McMaster</orgName></affiliation></author><author><name sortKey="Johnson, R L" sort="Johnson, R L" uniqKey="Johnson R" first="R. L." last="Johnson">R. L. Johnson</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Medicinal Chemistry, University of Minnesota</s1><s2>Minneapolis, Minnesota 55455</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Minneapolis, Minnesota 55455</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Journal of medicinal chemistry</title><title level="j" type="abbreviated">J. med. chem.</title><idno type="ISSN">0022-2623</idno><imprint><date when="1999">1999</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of medicinal chemistry</title><title level="j" type="abbreviated">J. med. chem.</title><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Affinity</term><term>Animal</term><term>Antiparkinson agent</term><term>Biological fixation</term><term>Carboxamide</term><term>Chemical synthesis</term><term>Chemotherapy</term><term>D2 Dopamine receptor</term><term>Experimental disease</term><term>In vitro</term><term>In vivo</term><term>Intraperitoneal administration</term><term>Lactam</term><term>Ligand</term><term>Modeling</term><term>Modulation</term><term>Molecular model</term><term>Molecular rigidity</term><term>Non peptide compound</term><term>Parkinson disease</term><term>Peptidomimetic compound</term><term>Rat</term><term>Spiran</term><term>Structure activity relation</term><term>Sulfur nitrogen heterocycle</term><term>Treatment</term><term>Tricyclic compound</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Relation structure activité</term><term>Synthèse chimique</term><term>Hétérocycle soufre azote</term><term>Composé tricyclique</term><term>Spirane</term><term>Lactame</term><term>Carboxamide</term><term>Composé peptidomimétique</term><term>Composé non peptide</term><term>Rigidité moléculaire</term><term>Modélisation</term><term>Modèle moléculaire</term><term>Modulation</term><term>Fixation biologique</term><term>Affinité</term><term>Ligand</term><term>Récepteur dopaminergique D2</term><term>In vitro</term><term>In vivo</term><term>Rat</term><term>Animal</term><term>Voie intrapéritonéale</term><term>Antiparkinsonien</term><term>Pathologie expérimentale</term><term>Chimiothérapie</term><term>Traitement</term><term>Parkinson maladie</term><term>Spiro[pyrrolidine-2:7'-pyrrolo[2,1-b]thiazine-4'-carboxylique acide] dérivé</term><term>Spiro[pyrrolidine-2:6'-thiazolidino[3,2-a]pipéridine-3'carboxylique acide] dérivé</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In the present study, the synthesis of the 5.5.6. and 5.6.5. spiro bicyclic lactam PLG peptidomimetics, compounds 3 and 4, respectively, was undertaken. These peptidomimetics were designed to examine the following: (1) the effect that changing the size of the thiazolidine and lactam ring systems would have on the ability of these systems to mimic the type-II β-turn and (2) the effect that these structural perturbations would have on the ability of the peptidomimetics to modulate dopamine receptors. Through the use of the [<sup>3</sup>H]spiroperidol/N-propylnorapomorphine (NPA) dopamine D<sub>2</sub> receptor competitive binding assay, 3 and 4, at a concentration of 100 nM, decreased the dissociation constant of the high-affinity state of the dopamine receptor for the agonist. These effects were observed when either Gpp(NH)p was absent or present and they were comparable to those produced by PLG at a concentration of 1 μM. Peptidomimetics 3 and 4 also increased the percentage of D<sub>2</sub> receptors that existed in the high-affinity state. Even with Gpp(NH)p present, 3 and 4 were able to return the R<sub>H</sub>/R<sub>L</sub> ratios to values observed in the respective controls where Gpp(NH)p was absent. Furthermore, both peptidomimetics were able to attenuate the Gpp(NH)p-induced shift to the low-affinity state to a greater extent than PLG. Peptidomimetics 3 and 4 were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism, and each affected the rotational behavior in a bell-shaped dose-response relationship producing increases of 95 ± 31% (0.01 mg/kg, ip) and 88 ± 14% (0.001 mg/kg, ip), respectively. In comparison, the previously reported 5.5.5. spiro bicyclic lactam 2 increased rotational behavior by 25 ± 11% (0.01 mg/kg, ip).</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Ontario</li></region><settlement><li>Hamilton (Ontario)</li></settlement><orgName><li>Université McMaster</li></orgName></list><tree><country name="États-Unis"><noRegion><name sortKey="Khalil, E M" sort="Khalil, E M" uniqKey="Khalil E" first="E. M." last="Khalil">E. M. Khalil</name></noRegion><name sortKey="Gleason, W B" sort="Gleason, W B" uniqKey="Gleason W" first="W. B." last="Gleason">W. B. Gleason</name><name sortKey="Johnson, R L" sort="Johnson, R L" uniqKey="Johnson R" first="R. L." last="Johnson">R. L. Johnson</name><name sortKey="Ojala, W H" sort="Ojala, W H" uniqKey="Ojala W" first="W. H." last="Ojala">W. H. Ojala</name></country><country name="Canada"><region name="Ontario"><name sortKey="Pradhan, A" sort="Pradhan, A" uniqKey="Pradhan A" first="A." last="Pradhan">A. Pradhan</name></region><name sortKey="Mishra, R K" sort="Mishra, R K" uniqKey="Mishra R" first="R. K." last="Mishra">R. K. Mishra</name><name sortKey="Nair, V D" sort="Nair, V D" uniqKey="Nair V" first="V. D." last="Nair">V. D. Nair</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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