The δ‐opioid receptor positive allosteric modulator BMS 986187 is a G‐protein‐biased allosteric agonist

Background and Purpose The δ‐opioid receptor is an emerging target for the management of chronic pain and depression. Biased signalling, the preferential activation of one signalling pathway over another downstream of δ‐receptors, may generate better therapeutic profiles. BMS 986187 is a positive allosteric modulator of δ‐receptors. Here, we ask if BMS 986187 can directly activate the receptor from an allosteric site, without an orthosteric ligand, and if a signalling bias is generated. Experimental Approach We used several clonal cell lines expressing δ‐receptors, to assess effects of BMS 986187 on events downstream of δ‐receptors by measuring G‐protein activation, β‐arrestin 2 recruitment, receptor phosphorylation, loss of surface receptor expression, ERK1/ERK2 phosphorylation, and receptor desensitization. Key Results BMS 986187 is a G protein biased allosteric agonist, relative to β‐arrestin 2 recruitment. Despite showing direct and potent G protein activation, BMS 986187 has a low potency to recruit β‐arrestin 2. This appears to reflect the inability of BMS 986187 to elicit any significant receptor phosphorylation, consistent with low receptor internalization and a slower onset of desensitization, compared with the full agonist SNC80. Conclusions and Implications This is the first evidence of biased agonism mediated through direct binding to an allosteric site on an opioid receptor, without a ligand at the orthosteric site. Our data suggest that agonists targeting δ‐receptors, or indeed any GPCR, through allosteric sites may be a novel way to promote signalling bias and thereby potentially produce a more specific pharmacology than can be observed by activation via the orthosteric site.