12 research outputs found
Discovery and Pharmacological Evaluation of a Diphenethylamine Derivative (HS665), a Highly Potent and Selective κ Opioid Receptor Agonist
Here we report on the design, synthesis, and biological
characterization
of novel κ opioid (KOP) receptor ligands of diphenethylamines.
In opioid receptor binding and functional assays, the <i>N</i>-cyclobutylmethyl substituted derivative <b>4</b> (HS665) showed
the highest affinity and selectivity for the KOP receptor and KOP
agonist potency. Compound <b>4</b> inhibited acetic acid induced
writhing after subcutaneous administration in mice via KOP receptor-mediated
mechanisms, being equipotent as an analgesic to the KOP agonist U50,488
<i>In vitro</i> agonist potency and efficacy.
a<p>Membranes from CHO cells stably transfected with human MOP, DOP or KOP receptors were used.</p>b<p>CHO cells co-expressing chimeric G proteins and recombinant human MOP, DOP or KOP receptors.</p>c<p>E<sub>max</sub> is expressed in percentage relative to maximal stimulation produced by DAMGO (MOP), DPDPE (DOP) or U69,593 (KOP).</p>d<p>Inactive up to 10 µM.</p>e<p>crc, concentration response curve.</p>f<p>ND, not determined due to very low binding affinity at the KOP receptor.</p><p>Values represent the mean ± SEM of at least three experiments each performed in duplicate or triplicate.</p
Antinociceptive activities.
a<p>Antinociceptive potencies determined 30 min after s.c. drug administration in mice shown as ED<sub>50</sub> values with 95% confidence limits (95% CL) (<i>n</i> = 5–6 mice per group).</p
Opioid receptor binding affinities and selectivities at MOP, DOP and KOP receptors.
<p>Binding assays were performed with membranes from rat brain (MOP and DOP receptors) and guinea pig brain (KOP receptors).</p><p>Values represent the mean ± SEM of at least three experiments each performed in duplicate.</p
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 <b>1</b> (HS665) and <b>2</b> (HS666).
A library of new diphenethylamines was designed, synthesized, and
pharmacologically evaluated. In comparison with <b>1</b> and <b>2</b>, 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, <b>1</b> and <b>2</b> in the writhing assay and without inducing motor dysfunction after
sc administration in mice
Dose-dependent antinociceptive effects produced by morphine, oxymorphone and <i>N</i>-methylmorphinans 1, 4 and 6.
<p>(A) Hot-plate test. (B) Tail-flick test. Hot-plate and tail-flick latencies (as %MPE) are shown at 30 min (peak of action) after s.c. drug administration to mice. Data are shown as the mean ± SEM (<i>n</i> = 5–6 mice per group).</p
Time-course of antinociceptive effects produced by morphine, oxymorphone and <i>N</i>-methylmorphinans 1, 4 and 6.
<p>The effect of morphine (1.25–5 mg/kg), oxymorphone (0.2–1 mg/kg), and compounds <b>1</b> (0.05–0.5 mg/kg), <b>4</b> (0.5–5 mg/kg), and <b>6</b> (0.1–0.5 mg/kg) in the hot-plate test (A, left panel) and in the tail-flick test (B, right panel). Hot-plate and tail-flick latencies (in seconds) were determined in mice before (0 min) and after s.c. drug administration (30, 60 and 120 min). Data are shown as the mean ± SEM (<i>n</i> = 5–6 mice per group).</p
<i>In vitro</i> agonist activities at the MOP receptor of morphine, oxymorphone and <i>N</i>-methylmorphinans 1, 4 and 6.
<p>Concentration-response curves in (A) [<sup>35</sup>S]GTPγS functional assay with membranes from CHO expressing human MOP receptor and (B) calcium mobilization experiments performed with CHO cells co-expressing the human MOP receptor and the Gα<sub>qi5</sub> protein. Activity is calculated as percentage of maximal stimulation produced by DAMGO. Data are shown as the mean ± SEM (<i>n</i>≥3).</p
Synthesis, Pharmacology, and Molecular Docking Studies on 6‑Desoxo‑<i>N</i>‑methylmorphinans as Potent μ‑Opioid Receptor Agonists
Position
6 of the morphinan skeleton plays a key role in the μ-opioid
receptor (MOR) activity in vitro and in vivo. We describe the consequence
of the 6-carbonyl group deletion in <i>N</i>-methylmorphinan-6-ones <b>1</b>–<b>4</b> on ligand–MOR interaction,
signaling, and antinociception. While 6-desoxo compounds <b>1a</b>, <b>2a</b>, and <b>4a</b> show similar profiles to their
6-keto counterparts, the 6-desoxo-14-benzyloxy substituted <b>3a</b> displays significantly increased MOR binding and agonist potency
and a distinct binding mode compared with its analogue <b>3</b>