SAR Matrices Enable Discovery of Mixed Efficacy μ‑Opioid Receptor Agonist Peptidomimetics with Simplified Structures through an Aromatic-Amine Pharmacophore

We
previously described the development of potent μ-opioid
receptor (MOR)-agonist/δ-opioid receptor (DOR)-antagonist peptidomimetic
ligands as an approach toward effective analgesics with reduced side
effects. In this series, a tetrahydroquinoline (THQ) or substituted
phenyl is employed to link two key pharmacophore elements, a dimethyltyrosine
amino acid and typically an aromatic pendant. Using new and previously
reported analogues, we constructed a structure–activity relationship
(SAR) matrix that probes the utility of previously reported amine
pendants. This matrix reveals that the MOR-agonist/DOR-antagonist
properties of these ligands do not change when a tetrahydroisoquinoline
(THIQ) pendant is used, despite removal of substituents on the core
phenyl ring. Based on this observation, we retained the THIQ pendant
and replaced the phenyl core with simpler aliphatic chain structures.
These simpler analogues proved to be potent MOR-agonists with high
variability in their effects at the DOR and the κ-opioid receptor
(KOR). These data show that the amine of the THIQ pendant may be a
novel pharmacophore element that favors high MOR-efficacy, whereas
the aromatic ring of the THIQ pendant may produce high MOR-potency.
Combined, the two pharmacophores within the THIQ pendant may be a
structurally efficient means of converting opioid peptides and peptidomimetics
into potent and efficacious MOR-agonists.