Dopamine receptors labelled by PHNO
Identifieur interne : 004415 ( Main/Exploration ); précédent : 004414; suivant : 004416Dopamine receptors labelled by PHNO
Auteurs : Philip Seeman [Canada] ; Carla Ulpian [Canada] ; Robert D. Larsen [États-Unis] ; Paul S. Anderson [États-Unis]Source :
- Synapse [ 0887-4476 ] ; 1993-08.
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Abstract
Since the high‐affinity state of dopamine D2 receptors may be abnormal in psychomotor diseases, it is desirable to develop a radioactive agonist to label this high‐affinity site for possible clinical diagnostic use. (+)PHNO is a selective D2 agonist used to treat Parkinson's disease. We prepared [3H](+)PHNO from allyl‐des‐propyl‐(+)PHNO. In binding to dopamine receptors in homogenates of canine brain striata, [3H](+)PHNO had a dissociation constant of 0.35 nM in the absence of NaCl, and 0.56 nM in the presence of NaCl. Dopamine agonists and antagonists inhibited the binding of [3H](+)PHNO at drug concentrations similar to those inhibiting other [3H]ligands at D2 receptors, but not similar to those acting at D4 receptors. Approximately 90% of the total [3H](+)PHNO binding was specific. Guanilylimidodiphosphate markedly inhibited [3H](+)PHNO binding, suggesting that [3H](+)PHNO was binding primarily to the high‐affinity state of dopamine D2 receptors rather than to D3 receptors. The density of the [3H](+)PHNO binding sites was equal to that of [3H]emonapride (or [3H]YM‐09151‐2), both densities of which were 1.5‐ to 2‐fold higher than that of [3H]spiperone, compatible with the idea that [3H](+)PHNO binds to monomers of D2, while [3H]spiperone binds to dimers of D2. Although [3H](+)PHNO has good selectivity and affinity for the high‐affinity state of D2, the [3H]ligand was sensitive to endogenous dopamine, since washing the tissue lowered the dissociation constant. For future in vivo labelling of D2 by an agonist, therefore, it will be essential to search for a related [3H]ligand with an even lower dissociation constant. © 1993 Wiley‐Liss, Inc.
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DOI: 10.1002/syn.890140403
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Anderson</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Merck Sharp and Dohme Research Laboratories, West Point</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j">Synapse</title><title level="j" type="abbrev">Synapse</title><idno type="ISSN">0887-4476</idno><idno type="eISSN">1098-2396</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="1993-08">1993-08</date><biblScope unit="volume">14</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="254">254</biblScope><biblScope unit="page" to="262">262</biblScope></imprint><idno type="ISSN">0887-4476</idno></series><idno type="istex">5386B7838B7BAC209F799F66FD5762D2C8FA7E3D</idno><idno type="DOI">10.1002/syn.890140403</idno><idno type="ArticleID">SYN890140403</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0887-4476</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antipsychotic drugs</term><term>Dopamine receptors</term><term>Endogenous dopamine</term><term>Neuroleptics</term><term>Parkinson's disease</term><term>Positron emission tomography</term><term>Schizophrenia</term><term>[3H](+)PHNO</term><term>[3H]Emonapride</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Since the high‐affinity state of dopamine D2 receptors may be abnormal in psychomotor diseases, it is desirable to develop a radioactive agonist to label this high‐affinity site for possible clinical diagnostic use. (+)PHNO is a selective D2 agonist used to treat Parkinson's disease. We prepared [3H](+)PHNO from allyl‐des‐propyl‐(+)PHNO. In binding to dopamine receptors in homogenates of canine brain striata, [3H](+)PHNO had a dissociation constant of 0.35 nM in the absence of NaCl, and 0.56 nM in the presence of NaCl. Dopamine agonists and antagonists inhibited the binding of [3H](+)PHNO at drug concentrations similar to those inhibiting other [3H]ligands at D2 receptors, but not similar to those acting at D4 receptors. Approximately 90% of the total [3H](+)PHNO binding was specific. Guanilylimidodiphosphate markedly inhibited [3H](+)PHNO binding, suggesting that [3H](+)PHNO was binding primarily to the high‐affinity state of dopamine D2 receptors rather than to D3 receptors. The density of the [3H](+)PHNO binding sites was equal to that of [3H]emonapride (or [3H]YM‐09151‐2), both densities of which were 1.5‐ to 2‐fold higher than that of [3H]spiperone, compatible with the idea that [3H](+)PHNO binds to monomers of D2, while [3H]spiperone binds to dimers of D2. Although [3H](+)PHNO has good selectivity and affinity for the high‐affinity state of D2, the [3H]ligand was sensitive to endogenous dopamine, since washing the tissue lowered the dissociation constant. For future in vivo labelling of D2 by an agonist, therefore, it will be essential to search for a related [3H]ligand with an even lower dissociation constant. © 1993 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>New Jersey</li><li>Ontario</li><li>Pennsylvanie</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><region name="Ontario"><name sortKey="Seeman, Philip" sort="Seeman, Philip" uniqKey="Seeman P" first="Philip" last="Seeman">Philip Seeman</name></region><name sortKey="Ulpian, Carla" sort="Ulpian, Carla" uniqKey="Ulpian C" first="Carla" last="Ulpian">Carla Ulpian</name></country><country name="États-Unis"><region name="New Jersey"><name sortKey="Larsen, Robert D" sort="Larsen, Robert D" uniqKey="Larsen R" first="Robert D." last="Larsen">Robert D. Larsen</name></region><name sortKey="Anderson, Paul S" sort="Anderson, Paul S" uniqKey="Anderson P" first="Paul S." last="Anderson">Paul S. Anderson</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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