Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor.

Bertini, Simone; Chicca, Andrea; Gado, Francesca; Arena, Chiara; Nieri, Daniela; Digiacomo, Maria; Saccomanni, Giuseppe; Zhao, Pingwei; Abood, Mary E; Macchia, Marco; Gertsch, Jürg; Manera, Clementina (2017). Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor. Bioorganic & medicinal chemistry, 25(24), pp. 6427-6434. Elsevier 10.1016/j.bmc.2017.10.015

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In this work, we explored the molecular framework of the known CB1R allosteric modulator PSNCBAM-1 with the aim to generate new bioactive analogs and to deepen the structure-activity relationships of this type of compounds. In particular, the introduction of a NH group between the pyridine ring and the phenyl nucleus generated the amino-phenyl-urea derivative SN15b that behaved as a positive allosteric modulator (PAM), increasing the CB1R binding affinity of the orthosteric ligand CP55,940. The functional activity was evaluated using serum response element (SRE) assay, which assesses the CB1R-dependent activation of the MAPK/ERK signaling pathway. SN15b and the biphenyl-urea analog SC4a significantly inhibited the response produced by CP55,940 in the low µM range, thus behaving as negative allosteric modulators (NAMs). The new derivatives presented here provide further insights about the modulation of CB1R binding and functional activity by allosteric ligands.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Chicca, Andrea; Nieri, Daniela and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0968-0896

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

19 Feb 2018 11:15

Last Modified:

31 Oct 2019 17:51

Publisher DOI:

10.1016/j.bmc.2017.10.015

PubMed ID:

29079014

Additional Information:

Simone Bertini and Andrea Chicca contributed equally to this work.

Uncontrolled Keywords:

Allosteric modulator CB1 receptor Endocannabinoid system MAPK/ERK signaling pathway Serum response element

BORIS DOI:

10.7892/boris.111380

URI:

https://boris.unibe.ch/id/eprint/111380

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