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Bioorg Med Chem. 2017 Dec 15;25(24):6427-6434. doi: 10.1016/j.bmc.2017.10.015. Epub 2017 Oct 16.

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

Author information

1
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
2
Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
3
Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
4
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. Electronic address: clementina.manera@unipi.it.

Abstract

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.

KEYWORDS:

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

PMID:
29079014
PMCID:
PMC5794004
DOI:
10.1016/j.bmc.2017.10.015
[Indexed for MEDLINE]
Free PMC Article

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