期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 1, 页码 276-287出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00368
关键词
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资金
- University of Pisa, Italy (Progetti di Ricerca di Ateneo) [PRA_2017_51]
- Fism-Fondazione Italiana Sclerosi Multipla [2017/R/16]
- 5 per mille public funding
The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects; therefore several CBRs ligands have been synthesized and tested in vitro and in vivo. However, none of them reached an advanced phase of clinical development due mainly to side effects on the CNS. Medicinal chemistry approaches are now engaged to develop allosteric modulators that might offer a novel therapeutic approach to achieve potential therapeutic benefits avoiding inherent side effects of orthosteric ligands. Here we identify the first ever synthesized positive-allosterk modulator (PAM) that targets CB(2)Rs. The evidence for this was obtained using [H-3]CP55940 and [S-35]GTP gamma S binding assays. This finding will be useful for the characterization of allosteric binding site(s) on CB(2)Rs which will be essential for the further development of CB2R allosteric modulators. Moreover, the new CB2R PAM displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain, raising the possibility that it might be a good candidate for clinical development.
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