SrasV1, France, Analysis, bibRecord, 000073

Structure–activity relationships and computational investigations into the development of potent and balanced dual-acting butyrylcholinesterase inhibitors and human cannabinoid receptor 2 ligands with pro-cognitive in vivo profiles

Identifieur interne : 000073 ( France/Analysis ); précédent : 000072; suivant : 000074

Structure–activity relationships and computational investigations into the development of potent and balanced dual-acting butyrylcholinesterase inhibitors and human cannabinoid receptor 2 ligands with pro-cognitive in vivo profiles

Auteurs : Dominik Dolles [Allemagne] ; Matthias Hoffmann [Allemagne] ; Sandra Gunesch [Allemagne] ; Oliviero Marinelli [Italie] ; Jan Möller [Allemagne] ; Giorgio Santoni [Italie] ; Arnaud Chatonnet [France] ; Martin J. Lohse [Allemagne] ; Hans-Joachim Wittmann [Allemagne] ; Andrea Strasser [Allemagne] ; Massimo Nabissi [Italie] ; Tangui Maurice [France] ; Michael Decker [Allemagne]

Source :

Journal of Medicinal Chemistry [ 0022-2623 ] ; 2018.

RBID : Hal:hal-01837661

Abstract

The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promisingtargets for pharmacotherapy in the later stages of Alzheimer’s disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted μ-opioid receptor affinitycould be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.

Url:

https://hal.archives-ouvertes.fr/hal-01837661

DOI: 10.1021/acs.jmedchem.7b01760

Affiliations:

Allemagne, France, Italie

Links toward previous steps (curation, corpus...)

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to stream France, to step Extraction: 000073

Links to Exploration step

Hal:hal-01837661

Le document en format XML

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          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
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        <tutelles><tutelle active="#struct-539024" type="direct"><org type="institution" xml:id="struct-539024" status="INCOMING">          <orgName>Julius Maximilian University</orgName>
          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>Allemagne</country>
</affiliation>
</author>
<author><name sortKey="Santoni, Giorgio" sort="Santoni, Giorgio" uniqKey="Santoni G" first="Giorgio" last="Santoni">Giorgio Santoni</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-539026" status="INCOMING">          <orgName>School of Pharmacy, Department of Experimental Medicine</orgName>
          <desc>            <address>              <country key="IT"></country>
            </address>
          </desc>
          <listRelation>            <relation active="#struct-473150" type="direct"></relation>
          </listRelation>
        <tutelles><tutelle active="#struct-473150" type="direct"><org type="institution" xml:id="struct-473150" status="VALID">          <orgName>University of Camerino</orgName>
          <date type="start">2016-11-24</date>
          <desc>            <address>              <country key="IT"></country>
            </address>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>Italie</country>
</affiliation>
</author>
<author><name sortKey="Chatonnet, Arnaud" sort="Chatonnet, Arnaud" uniqKey="Chatonnet A" first="Arnaud" last="Chatonnet">Arnaud Chatonnet</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-206262" status="OLD">          <idno type="RNSR">199917397U</idno>
          <orgName>Dynamique Musculaire et Métabolisme</orgName>
          <orgName type="acronym">DMEM</orgName>
          <date type="end">2019-12-31</date>
          <desc>            <address>              <addrLine>INRA 2 place Viala 34060 Montpellier Cedex 1</addrLine>
              <country key="FR"></country>
            </address>
            <ref type="url">http://www6.montpellier.inra.fr/dmem/</ref>
          </desc>
          <listRelation>            <relation name="UMR 0866" active="#struct-410122" type="direct"></relation>
            <relation active="#struct-92114" type="direct"></relation>
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        <tutelles><tutelle name="UMR 0866" active="#struct-410122" type="direct"><org type="institution" xml:id="struct-410122" status="VALID">          <idno type="ISNI">0000000120970141</idno>
          <orgName>Université de Montpellier</orgName>
          <orgName type="acronym">UM</orgName>
          <desc>            <address>              <addrLine>163 rue Auguste Broussonnet - 34090 Montpellier</addrLine>
              <country key="FR"></country>
            </address>
            <ref type="url">http://www.umontpellier.fr/</ref>
          </desc>
        </org>
</tutelle>
<tutelle active="#struct-92114" type="direct"><org type="institution" xml:id="struct-92114" status="OLD">          <orgName>Institut National de la Recherche Agronomique</orgName>
          <orgName type="acronym">INRA</orgName>
          <date type="start">1946-05-18</date>
          <date type="end">2019-12-31</date>
          <desc>            <address>              <country key="FR"></country>
            </address>
            <ref type="url">http://www.inra.fr</ref>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>France</country>
</affiliation>
</author>
<author><name sortKey="Lohse, Martin J" sort="Lohse, Martin J" uniqKey="Lohse M" first="Martin J." last="Lohse">Martin J. Lohse</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-539027" status="INCOMING">          <orgName>Institute of Pharmacology and Toxicology</orgName>
          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
          <listRelation>            <relation active="#struct-539024" type="direct"></relation>
          </listRelation>
        <tutelles><tutelle active="#struct-539024" type="direct"><org type="institution" xml:id="struct-539024" status="INCOMING">          <orgName>Julius Maximilian University</orgName>
          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>Allemagne</country>
</affiliation>
</author>
<author><name sortKey="Wittmann, Hans Joachim" sort="Wittmann, Hans Joachim" uniqKey="Wittmann H" first="Hans-Joachim" last="Wittmann">Hans-Joachim Wittmann</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-539028" status="INCOMING">          <orgName>Pharmaceutical and Medicinal Chemistry II, Institute of Pharmacy</orgName>
          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
          <listRelation>            <relation active="#struct-303027" type="direct"></relation>
          </listRelation>
        <tutelles><tutelle active="#struct-303027" type="direct"><org type="institution" xml:id="struct-303027" status="VALID">          <orgName>Universität Regensburg</orgName>
          <orgName type="acronym">UR</orgName>
          <date type="start">2016-10-17</date>
          <desc>            <address>              <addrLine>Universitätsstraße 31, 93053 Regensburg</addrLine>
              <country key="DE"></country>
            </address>
            <ref type="url">http://www.uni-regensburg.de</ref>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>Allemagne</country>
</affiliation>
</author>
<author><name sortKey="Strasser, Andrea" sort="Strasser, Andrea" uniqKey="Strasser A" first="Andrea" last="Strasser">Andrea Strasser</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-539028" status="INCOMING">          <orgName>Pharmaceutical and Medicinal Chemistry II, Institute of Pharmacy</orgName>
          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
          <listRelation>            <relation active="#struct-303027" type="direct"></relation>
          </listRelation>
        <tutelles><tutelle active="#struct-303027" type="direct"><org type="institution" xml:id="struct-303027" status="VALID">          <orgName>Universität Regensburg</orgName>
          <orgName type="acronym">UR</orgName>
          <date type="start">2016-10-17</date>
          <desc>            <address>              <addrLine>Universitätsstraße 31, 93053 Regensburg</addrLine>
              <country key="DE"></country>
            </address>
            <ref type="url">http://www.uni-regensburg.de</ref>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>Allemagne</country>
</affiliation>
</author>
<author><name sortKey="Nabissi, Massimo" sort="Nabissi, Massimo" uniqKey="Nabissi M" first="Massimo" last="Nabissi">Massimo Nabissi</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-539026" status="INCOMING">          <orgName>School of Pharmacy, Department of Experimental Medicine</orgName>
          <desc>            <address>              <country key="IT"></country>
            </address>
          </desc>
          <listRelation>            <relation active="#struct-473150" type="direct"></relation>
          </listRelation>
        <tutelles><tutelle active="#struct-473150" type="direct"><org type="institution" xml:id="struct-473150" status="VALID">          <orgName>University of Camerino</orgName>
          <date type="start">2016-11-24</date>
          <desc>            <address>              <country key="IT"></country>
            </address>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>Italie</country>
</affiliation>
</author>
<author><name sortKey="Maurice, Tangui" sort="Maurice, Tangui" uniqKey="Maurice T" first="Tangui" last="Maurice">Tangui Maurice</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-3068" status="VALID">          <idno type="RNSR">200716389N</idno>
          <orgName>Mécanismes moléculaires dans les démences neurodégénératives</orgName>
          <orgName type="acronym">MMDN</orgName>
          <desc>            <address>              <addrLine>U1198 - Université de Montpellier, Place Eugène Bataillon 34095 Montpellier Cedex 5</addrLine>
              <country key="FR"></country>
            </address>
            <ref type="url">https://mmdn.umontpellier.fr/fr/</ref>
          </desc>
          <listRelation>            <relation name="U1198" active="#struct-303623" type="direct"></relation>
            <relation active="#struct-92690" type="direct"></relation>
            <relation name="UMR_S 1198" active="#struct-410122" type="direct"></relation>
            <relation active="#struct-110691" type="direct"></relation>
          </listRelation>
        <tutelles><tutelle name="U1198" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID">          <idno type="IdRef">026388278</idno>
          <orgName>Institut National de la Santé et de la Recherche Médicale</orgName>
          <orgName type="acronym">INSERM</orgName>
          <desc>            <address>              <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine>
              <country key="FR"></country>
            </address>
            <ref type="url">http://www.inserm.fr</ref>
          </desc>
        </org>
</tutelle>
<tutelle active="#struct-92690" type="direct"><org type="institution" xml:id="struct-92690" status="OLD">          <orgName>Université Montpellier 2 - Sciences et Techniques</orgName>
          <orgName type="acronym">UM2</orgName>
          <date type="end">2014-12-31</date>
          <desc>            <address>              <addrLine>Place Eugène Bataillon - 34095 Montpellier cedex 5</addrLine>
              <country key="FR"></country>
            </address>
            <ref type="url">http://www.univ-montp2.fr/</ref>
          </desc>
        </org>
</tutelle>
<tutelle name="UMR_S 1198" active="#struct-410122" type="direct"><org type="institution" xml:id="struct-410122" status="VALID">          <idno type="ISNI">0000000120970141</idno>
          <orgName>Université de Montpellier</orgName>
          <orgName type="acronym">UM</orgName>
          <desc>            <address>              <addrLine>163 rue Auguste Broussonnet - 34090 Montpellier</addrLine>
              <country key="FR"></country>
            </address>
            <ref type="url">http://www.umontpellier.fr/</ref>
          </desc>
        </org>
</tutelle>
<tutelle active="#struct-110691" type="direct"><org type="institution" xml:id="struct-110691" status="VALID">          <orgName>École pratique des hautes études</orgName>
          <orgName type="acronym">EPHE</orgName>
          <desc>            <address>              <addrLine>4-14 Rue Ferrus, 75014 Paris</addrLine>
              <country key="FR"></country>
            </address>
            <ref type="url">http://www.ephe.fr</ref>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>France</country>
</affiliation>
</author>
<author><name sortKey="Decker, Michael" sort="Decker, Michael" uniqKey="Decker M" first="Michael" last="Decker">Michael Decker</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-539025" status="INCOMING">          <orgName>Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry </orgName>
          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
          <listRelation>            <relation active="#struct-539024" type="direct"></relation>
          </listRelation>
        <tutelles><tutelle active="#struct-539024" type="direct"><org type="institution" xml:id="struct-539024" status="INCOMING">          <orgName>Julius Maximilian University</orgName>
          <desc>            <address>              <country key="DE"></country>
            </address>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>Allemagne</country>
</affiliation>
</author>
</analytic>
<idno type="DOI">10.1021/acs.jmedchem.7b01760</idno>
<series><title level="j">Journal of Medicinal Chemistry</title>
<idno type="ISSN">0022-2623</idno>
<imprint><date type="datePub">2018</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">              <p>The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promisingtargets for pharmacotherapy in the later stages of Alzheimer’s disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted μ-opioid receptor affinitycould be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.</p>
            </div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>France</li>
<li>Italie</li>
</country>
</list>
<tree><country name="Allemagne"><noRegion><name sortKey="Dolles, Dominik" sort="Dolles, Dominik" uniqKey="Dolles D" first="Dominik" last="Dolles">Dominik Dolles</name>
</noRegion>
<name sortKey="Decker, Michael" sort="Decker, Michael" uniqKey="Decker M" first="Michael" last="Decker">Michael Decker</name>
<name sortKey="Gunesch, Sandra" sort="Gunesch, Sandra" uniqKey="Gunesch S" first="Sandra" last="Gunesch">Sandra Gunesch</name>
<name sortKey="Hoffmann, Matthias" sort="Hoffmann, Matthias" uniqKey="Hoffmann M" first="Matthias" last="Hoffmann">Matthias Hoffmann</name>
<name sortKey="Lohse, Martin J" sort="Lohse, Martin J" uniqKey="Lohse M" first="Martin J." last="Lohse">Martin J. Lohse</name>
<name sortKey="Moller, Jan" sort="Moller, Jan" uniqKey="Moller J" first="Jan" last="Möller">Jan Möller</name>
<name sortKey="Strasser, Andrea" sort="Strasser, Andrea" uniqKey="Strasser A" first="Andrea" last="Strasser">Andrea Strasser</name>
<name sortKey="Wittmann, Hans Joachim" sort="Wittmann, Hans Joachim" uniqKey="Wittmann H" first="Hans-Joachim" last="Wittmann">Hans-Joachim Wittmann</name>
</country>
<country name="Italie"><noRegion><name sortKey="Marinelli, Oliviero" sort="Marinelli, Oliviero" uniqKey="Marinelli O" first="Oliviero" last="Marinelli">Oliviero Marinelli</name>
</noRegion>
<name sortKey="Nabissi, Massimo" sort="Nabissi, Massimo" uniqKey="Nabissi M" first="Massimo" last="Nabissi">Massimo Nabissi</name>
<name sortKey="Santoni, Giorgio" sort="Santoni, Giorgio" uniqKey="Santoni G" first="Giorgio" last="Santoni">Giorgio Santoni</name>
</country>
<country name="France"><noRegion><name sortKey="Chatonnet, Arnaud" sort="Chatonnet, Arnaud" uniqKey="Chatonnet A" first="Arnaud" last="Chatonnet">Arnaud Chatonnet</name>
</noRegion>
<name sortKey="Maurice, Tangui" sort="Maurice, Tangui" uniqKey="Maurice T" first="Tangui" last="Maurice">Tangui Maurice</name>
</country>
</tree>
</affiliations>
</record>

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Structure–activity relationships and computational investigations into the development of potent and balanced dual-acting butyrylcholinesterase inhibitors and human cannabinoid receptor 2 ligands with pro-cognitive in vivo profiles

Structure–activity relationships and computational investigations into the development of potent and balanced dual-acting butyrylcholinesterase inhibitors and human cannabinoid receptor 2 ligands with pro-cognitive in vivo profiles

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