Highly Potent and Selective New Diphenethylamines Interacting with the κ‑Opioid Receptor: Synthesis, Pharmacology, and Structure–Activity Relationships

We
previously reported on a series of small molecules targeting
the κ-opioid (KOP) receptor featuring a diphenethylamine scaffold
and showed the promise of these ligands as effective analgesics with
reduced liability for adverse effects. This study expands the structure–activity
relationships on our original series by presenting several modifications
in the lead compounds 1 (HS665) and 2 (HS666).
A library of new diphenethylamines was designed, synthesized, and
pharmacologically evaluated. In comparison with 1 and 2, the KOP receptor affinity, selectivity, and agonist activity
were modulated by introducing bulkier N-substituents, a 2-fluoro substitution,
and additional hydroxyl groups at positions 3′ and 4′.
Several analogues showed subnanomolar affinity and excellent KOP receptor
selectivity acting as full or partial agonists, and one as an antagonist.
The new diphenethylamines displayed antinociceptive efficacies with
increased potencies than U50,488, 1 and 2 in the writhing assay and without inducing motor dysfunction after
sc administration in mice.