Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats
In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the prepar...
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| Veröffentlicht in: | European journal of medicinal chemistry 2019-10, Vol.179, p.449-469 |
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| creator | Ouach, Aziz Vercouillie, Johnny Bertrand, Emilie Rodrigues, Nuno Pin, Frederic Serriere, Sophie Boiaryna, Liliana Chartier, Agnes Percina, Nathalie Tangpong, Pakorn Gulhan, Zuhal Mothes, Celine Deloye, Jean-Bernard Guilloteau, Denis Page, Guylene Suzenet, Franck Buron, Frederic Chalon, Sylvie Routier, Sylvain |
| description | In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.
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•47 new potent triazole/quinuclidinic alpha 7 nAChR ligand have been synthesized.•Identified leads exhibited a affinity in the subnanomolar range (10 cpds with 0.2 |
| doi_str_mv | 10.1016/j.ejmech.2019.06.049 |
| format | Article |
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[Display omitted]
•47 new potent triazole/quinuclidinic alpha 7 nAChR ligand have been synthesized.•Identified leads exhibited a affinity in the subnanomolar range (10 cpds with 0.2 < Ki < 1 nM).•Leads exhibit strict selectivity toward the α4β2 nicotinic and 5-HT3 receptors.•Brain penetration and distribution was evaluated by preparing [18F] radiolabelled derivatives.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2019.06.049</identifier><identifier>PMID: 31271958</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>18F PET ; Agonism ; Alpha 7 nicotinic acetylcholine receptor ; Chemical Sciences ; Medicinal Chemistry ; Organic chemistry ; Quinuclidine ; Radiochemistry ; Radiolabeling ; SAR ; Triazole</subject><ispartof>European journal of medicinal chemistry, 2019-10, Vol.179, p.449-469</ispartof><rights>2019 Elsevier Masson SAS</rights><rights>Copyright © 2019 Elsevier Masson SAS. All rights reserved.</rights><rights>Attribution - NonCommercial</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3609-c4d58531feabdab9f307f05a5c4593c1fefd0c2fa7012b5d394245c011385df53</citedby><cites>FETCH-LOGICAL-c3609-c4d58531feabdab9f307f05a5c4593c1fefd0c2fa7012b5d394245c011385df53</cites><orcidid>0000-0003-1865-8380 ; 0000-0002-2823-0591 ; 0000-0001-5773-1515 ; 0000-0002-7474-7778 ; 0000-0002-7113-0254 ; 0000-0003-1394-1603 ; 0000-0003-4495-7755</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2019.06.049$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31271958$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-02458368$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Ouach, Aziz</creatorcontrib><creatorcontrib>Vercouillie, Johnny</creatorcontrib><creatorcontrib>Bertrand, Emilie</creatorcontrib><creatorcontrib>Rodrigues, Nuno</creatorcontrib><creatorcontrib>Pin, Frederic</creatorcontrib><creatorcontrib>Serriere, Sophie</creatorcontrib><creatorcontrib>Boiaryna, Liliana</creatorcontrib><creatorcontrib>Chartier, Agnes</creatorcontrib><creatorcontrib>Percina, Nathalie</creatorcontrib><creatorcontrib>Tangpong, Pakorn</creatorcontrib><creatorcontrib>Gulhan, Zuhal</creatorcontrib><creatorcontrib>Mothes, Celine</creatorcontrib><creatorcontrib>Deloye, Jean-Bernard</creatorcontrib><creatorcontrib>Guilloteau, Denis</creatorcontrib><creatorcontrib>Page, Guylene</creatorcontrib><creatorcontrib>Suzenet, Franck</creatorcontrib><creatorcontrib>Buron, Frederic</creatorcontrib><creatorcontrib>Chalon, Sylvie</creatorcontrib><creatorcontrib>Routier, Sylvain</creatorcontrib><title>Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.
[Display omitted]
•47 new potent triazole/quinuclidinic alpha 7 nAChR ligand have been synthesized.•Identified leads exhibited a affinity in the subnanomolar range (10 cpds with 0.2 < Ki < 1 nM).•Leads exhibit strict selectivity toward the α4β2 nicotinic and 5-HT3 receptors.•Brain penetration and distribution was evaluated by preparing [18F] radiolabelled derivatives.</description><subject>18F PET</subject><subject>Agonism</subject><subject>Alpha 7 nicotinic acetylcholine receptor</subject><subject>Chemical Sciences</subject><subject>Medicinal Chemistry</subject><subject>Organic chemistry</subject><subject>Quinuclidine</subject><subject>Radiochemistry</subject><subject>Radiolabeling</subject><subject>SAR</subject><subject>Triazole</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kd9qFDEUxgdR7Fp9A5FcVthZ82cyO-NFoZbWCgsK1iuRkE3O7JwlM9kmmYX1rXwG730mU7b20pscyPl93wfnK4rXjC4YZfW77QK2A5h-wSlrF7Re0Kp9UszYsm5KwWX1tJhRzkUpuahOihcxbimlsqb0eXEiGF-yVjaz4vcHjGc9pLc6HFzJ5nwuyhRQ__QOyN2E42QcWhwhEh3Jn19LMqLxCfNLtIF0cKb3Lu9JAAO75ANxuNGjje_J18OYeogY5ySmMJk0BSC667I4HTLvdEI_xh53mdAbP2IcsmnCfd7PyXfWXP8og7bonV5DDtmQbEy-XN1mv8keCI4k6BRfFs867SK8epinxbfrq9vLm3L1-eOny4tVaURN29JUVjZSsA702up12wm67KjU0lSyFSb_d5Ya3uklZXwtrWgrXklDGRONtJ0Up8X86Ntrp3YBh3wz5TWqm4uVwjFCGBTNkkbUzZ5l_OyI74K_myAmNWA04JwewU9RcS6FYLQWbUarI2qCjzFA92jPqLpvW23VsW1137aitcptZ9mbh4RpPYB9FP2rNwPnRwDyWfYIQUWDMBqwmOtKynr8f8Jf64XA8g</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Ouach, Aziz</creator><creator>Vercouillie, Johnny</creator><creator>Bertrand, Emilie</creator><creator>Rodrigues, Nuno</creator><creator>Pin, Frederic</creator><creator>Serriere, Sophie</creator><creator>Boiaryna, Liliana</creator><creator>Chartier, Agnes</creator><creator>Percina, Nathalie</creator><creator>Tangpong, Pakorn</creator><creator>Gulhan, Zuhal</creator><creator>Mothes, Celine</creator><creator>Deloye, Jean-Bernard</creator><creator>Guilloteau, Denis</creator><creator>Page, Guylene</creator><creator>Suzenet, Franck</creator><creator>Buron, Frederic</creator><creator>Chalon, Sylvie</creator><creator>Routier, Sylvain</creator><general>Elsevier Masson SAS</general><general>Elsevier</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0003-1865-8380</orcidid><orcidid>https://orcid.org/0000-0002-2823-0591</orcidid><orcidid>https://orcid.org/0000-0001-5773-1515</orcidid><orcidid>https://orcid.org/0000-0002-7474-7778</orcidid><orcidid>https://orcid.org/0000-0002-7113-0254</orcidid><orcidid>https://orcid.org/0000-0003-1394-1603</orcidid><orcidid>https://orcid.org/0000-0003-4495-7755</orcidid></search><sort><creationdate>20191001</creationdate><title>Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats</title><author>Ouach, Aziz ; 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The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.
[Display omitted]
•47 new potent triazole/quinuclidinic alpha 7 nAChR ligand have been synthesized.•Identified leads exhibited a affinity in the subnanomolar range (10 cpds with 0.2 < Ki < 1 nM).•Leads exhibit strict selectivity toward the α4β2 nicotinic and 5-HT3 receptors.•Brain penetration and distribution was evaluated by preparing [18F] radiolabelled derivatives.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>31271958</pmid><doi>10.1016/j.ejmech.2019.06.049</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0003-1865-8380</orcidid><orcidid>https://orcid.org/0000-0002-2823-0591</orcidid><orcidid>https://orcid.org/0000-0001-5773-1515</orcidid><orcidid>https://orcid.org/0000-0002-7474-7778</orcidid><orcidid>https://orcid.org/0000-0002-7113-0254</orcidid><orcidid>https://orcid.org/0000-0003-1394-1603</orcidid><orcidid>https://orcid.org/0000-0003-4495-7755</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Access via ScienceDirect (Elsevier) |
| subjects | 18F PET Agonism Alpha 7 nicotinic acetylcholine receptor Chemical Sciences Medicinal Chemistry Organic chemistry Quinuclidine Radiochemistry Radiolabeling SAR Triazole |
| title | Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [18F]-radiolabeling and PET study in rats |
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