The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine scaffold is a well-known pharmacophore for antagonism at mu-opioid (MOP), kappa-opioid (KOP), and delta-opioid (DOP) receptors, however; its pharmacological activity at the fourth opioid subtype, the nociceptin opioid (NOP/ORL-1) receptor, has not been explored. One derivative based on this scaffold is the KOP selective antagonist JDTic. In our laboratory, we discovered that JDTic has significant binding affinity at the NOP receptor (Ki NOP: 16.7 ± 0.8 nM), with no intrinsic activity in the [35S]GTPγS functional assay. In order to explore the structural determinants of JDTic binding for the NOP receptor, we performed rational chemical modifications of this scaffold. Removal of the two dimethyl groups of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine portion of JDTic resulted in a 10-fold increase in binding affinity at the NOP receptor compared to JDTic (Ki 1.75 ± 0.74 nM), while maintaining comparable affinity for KOP, MOP and DOP receptors (Ki 1.14 ± 0.63 nM, 1.67 ± 0.6 nM, 19.6 ± 1.3 nM, respectively), resulting in AT-076, an equipotent ligand at all four opioid receptors. Detailed in vitro characterization of the functional activity of AT-076 showed that it had a non-competitive antagonist profile at the NOP and KOP receptors, but was a potent competitive antagonist at the MOP and DOP receptors, with Ke values of 30 nM, 4 nM, 0.6 nM, and 25 nM, respectively. Our SAR suggests that the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist pharmacophore may not have optimal binding to the NOP receptor, compared to other opioid receptors. However, removal of the 3R,4R-dimethyl groups, retains affinity and antagonist potency at the opioid receptors, and increases affinity and antagonist potency at the NOP receptor, leading to a pan opioid antagonist. This work is supported by grant R01DA027811 and R01DA14026 (NZ).

Discovery and opioid receptor SAR of AT-076, the first small-molecule opioid pan antagonist with nanomolar affinity at mu, delta, kappa and nociceptin opioid receptors

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.