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Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1)
[Image: see text] The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (4) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on 4, we have designed and synthesized a series of analogs focusing on modifications at tw...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175001/ https://www.ncbi.nlm.nih.gov/pubmed/25162172 http://dx.doi.org/10.1021/jm501042u |
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author | German, Nadezhda Decker, Ann M. Gilmour, Brian P. Gay, Elaine A. Wiley, Jenny L. Thomas, Brian F. Zhang, Yanan |
author_facet | German, Nadezhda Decker, Ann M. Gilmour, Brian P. Gay, Elaine A. Wiley, Jenny L. Thomas, Brian F. Zhang, Yanan |
author_sort | German, Nadezhda |
collection | PubMed |
description | [Image: see text] The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (4) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on 4, we have designed and synthesized a series of analogs focusing on modifications at two positions. Pharmacological evaluation in calcium mobilization and binding assays revealed the importance of alkyl substitution at the 2-aminopyridine moiety and electron deficient aromatic groups at the 4-chlorophenyl position for activity at the CB1 receptor, resulting in several analogs with comparable potency to 4. These compounds increased the specific binding of [(3)H]CP55,940, in agreement with previous reports. Importantly, 4 and two analogs dose-dependently reduced the E(max) of the agonist curve in the CB1 calcium mobilization assays, confirming their negative allosteric modulator characteristics. Given the side effects associated with CB1 receptor orthosteric antagonists, negative allosteric modulators provide an alternative approach to modulate the pharmacologically important CB1 receptor. |
format | Online Article Text |
id | pubmed-4175001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-41750012015-08-27 Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1) German, Nadezhda Decker, Ann M. Gilmour, Brian P. Gay, Elaine A. Wiley, Jenny L. Thomas, Brian F. Zhang, Yanan J Med Chem [Image: see text] The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (4) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on 4, we have designed and synthesized a series of analogs focusing on modifications at two positions. Pharmacological evaluation in calcium mobilization and binding assays revealed the importance of alkyl substitution at the 2-aminopyridine moiety and electron deficient aromatic groups at the 4-chlorophenyl position for activity at the CB1 receptor, resulting in several analogs with comparable potency to 4. These compounds increased the specific binding of [(3)H]CP55,940, in agreement with previous reports. Importantly, 4 and two analogs dose-dependently reduced the E(max) of the agonist curve in the CB1 calcium mobilization assays, confirming their negative allosteric modulator characteristics. Given the side effects associated with CB1 receptor orthosteric antagonists, negative allosteric modulators provide an alternative approach to modulate the pharmacologically important CB1 receptor. American Chemical Society 2014-08-27 2014-09-25 /pmc/articles/PMC4175001/ /pubmed/25162172 http://dx.doi.org/10.1021/jm501042u Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
spellingShingle | German, Nadezhda Decker, Ann M. Gilmour, Brian P. Gay, Elaine A. Wiley, Jenny L. Thomas, Brian F. Zhang, Yanan Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1) |
title | Diarylureas as Allosteric
Modulators of the Cannabinoid
CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea
(PSNCBAM-1) |
title_full | Diarylureas as Allosteric
Modulators of the Cannabinoid
CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea
(PSNCBAM-1) |
title_fullStr | Diarylureas as Allosteric
Modulators of the Cannabinoid
CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea
(PSNCBAM-1) |
title_full_unstemmed | Diarylureas as Allosteric
Modulators of the Cannabinoid
CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea
(PSNCBAM-1) |
title_short | Diarylureas as Allosteric
Modulators of the Cannabinoid
CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea
(PSNCBAM-1) |
title_sort | diarylureas as allosteric
modulators of the cannabinoid
cb1 receptor: structure–activity relationship studies on 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea
(psncbam-1) |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175001/ https://www.ncbi.nlm.nih.gov/pubmed/25162172 http://dx.doi.org/10.1021/jm501042u |
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