7 research outputs found
Methylation Products of 6β‑<i>N</i>‑Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators
Two
6β-<i>N</i>-heterocyclic naltrexamine derivatives,
NAP and NMP, have been identified as peripherally selective mu opioid
receptor (MOR) antagonists. To further enhance the peripheral selectivity
of both compounds, the 17-amino group and the nitrogen atom of the
pyridine ring in both NAP and NMP were methylated to obtain dMNAP
and dMNMP, respectively. Compared with NAP and NMP, the binding affinities
of dMNAP and dMNMP shifted to MOR and KOR (kappa opioid receptor)
dual selective and they acted as moderate efficacy partial agonists.
The results from radioligand binding studies were further confirmed
by molecular docking studies. In vivo studies demonstrated that dMNAP
and dMNMP did not produce antinociception nor did they antagonize
morphine’s antinociceptive activity, indicating that these
compounds did not act on the central nervous system. Meanwhile, both
dMNAP and dMNMP significantly slowed down fecal excretion, which indicated
that they were peripherally acting opioid receptor agonists. All together,
these results suggested that dMNAP and dMNMP acted as peripheral mu/kappa
opioid receptor modulators and may be applicable in the treatment
of diarrhea in patients with bowel dysfunction
Nanoconjugated NAP as a Potent and Periphery Selective Mu Opioid Receptor Modulator To Treat Opioid-Induced Constipation
Opioids are the mainstay for cancer
and noncancer pain management.
However, their use is often associated with multiple adverse effects.
Among them, the most common and persistent one is probably opioid-induced
constipation (OIC). Periphery selective opioid antagonists may alleviate
the symptoms of OIC without compromising the analgesic effects of
opioids. Recently our laboratories have identified one novel lead
compound, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)Âacetamido]Âmorphinan
(NAP), as a peripherally selective mu opioid receptor ligand carrying
subnanomolar affinity to the mu opioid receptor and over 100-folds
of selectivity over both the delta and kappa opioid receptors, with
reasonable oral availability and half-life, and potential to treat
OIC. Nanoparticle-based drug delivery systems are now widely considered
due to their technological advantages such as good stability, high
carrier capacity, low therapeutic side effects, etc. Herein we report
nanoparticle supported NAP as a potential candidate for OIC treatment
with improved peripheral selectivity over the original lead compound
NAP
Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues
Discovery of analgesics void of abuse liability is critical
to
battle the opioid crisis in the United States. Among many strategies
to achieve this goal, targeting more than one opioid receptor seems
promising to minimize this unwanted side effect while achieving a
reasonable therapeutic profile. In the process of understanding the
structure–activity relationship of nalfurafine, we identified
a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta
opioid receptor agonist with minimum abuse liability. Further characterizations,
including primary in vitro ADMET studies (hERG toxicity, plasma protein
binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic
and toxicity profiling (time course, abuse liability, tolerance, withdrawal,
respiratory depression, body weight, and locomotor activity) further
confirmed NMF as a promising drug candidate for future development
Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues
Discovery of analgesics void of abuse liability is critical
to
battle the opioid crisis in the United States. Among many strategies
to achieve this goal, targeting more than one opioid receptor seems
promising to minimize this unwanted side effect while achieving a
reasonable therapeutic profile. In the process of understanding the
structure–activity relationship of nalfurafine, we identified
a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta
opioid receptor agonist with minimum abuse liability. Further characterizations,
including primary in vitro ADMET studies (hERG toxicity, plasma protein
binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic
and toxicity profiling (time course, abuse liability, tolerance, withdrawal,
respiratory depression, body weight, and locomotor activity) further
confirmed NMF as a promising drug candidate for future development
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4′-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion
Mounting
evidence has suggested that G protein-coupled receptors
can be stabilized in multiple conformations in response to distinct
ligands, which exert discrete functions through selective activation
of various downstream signaling events. In accordance with this concept,
we report biased signaling of one C6-heterocyclic substituted naltrexamine
derivative, namely, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4′-pyridylcarboxamido)Âmorphinan
(NAP) at the mu opioid receptor (MOR). NAP acted as a low efficacy
MOR partial agonist in the G protein-mediated [<sup>35</sup>S]ÂGTPγS
binding assay, whereas it did not significantly induce calcium flux
or β-arrestin2 recruitment. In contrast, it potently blocked
MOR full agonist-induced β-arrestin2 recruitment and translocation.
Additionally, NAP dose-dependently antagonized MOR full agonist-induced
intracellular calcium flux and β-arrestin2 recruitment. Further
results in an isolated organ bath preparation confirmed that NAP reversed
the morphine-induced reduction in colon motility. Ligand docking and
dynamics simulation studies of NAP at the MOR provided more supporting
evidence for biased signaling of NAP at an atomic level. Due to the
fact that NAP is MOR selective and preferentially distributed peripherally
upon systemic administration while β-arrestin2 is reportedly
required for impairment of intestinal motility by morphine, biased
antagonism of β-arrestin2 recruitment by NAP further supports
its utility as a treatment for opioid-induced constipation
6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand
The
6β-N-heterocyclic naltrexamine derivative, NAP, has been demonstrated
to be a peripherally selective mu opioid receptor modulator. To further
improve peripheral selectivity of this highly potent ligand, its pyridal
ring was quaterinized with benzyl bromide to produce BNAP. In radioligand
binding assay, the <i>K</i><sub>i</sub> of BNAP for MOR
was 0.76 ± 0.09 nM and was >900-fold more selective for MOR
than DOR. The <i>K</i><sub>i</sub> for KOR was 3.46 ±
0.05 nM. In [<sup>35</sup>S]ÂGTPγS ligand stimulated assay, BNAP
showed low agonist efficacy with 14.6% of the maximum response of
DAMGO with an EC<sub>50</sub> of 4.84 ± 0.6 nM. However, unlike
its parent compound NAP, BNAP displayed partial agonist activity at
KOR with % maximum response at 45.9 ± 1.7% of U50,488H. BNAP
did not reverse morphine-induced antinociception when administered
subcutaneously but did antagonize when administered intracerebroventricularly.
BNAP antagonized morphine-induced contractions of the circular muscle
in mice colon. BNAP inhibition of field-stimulated contractions in
longitudinal muscle strips for the guinea-pig ileum were also blocked
by nor-BNI, a kappa opioid receptor antagonist. BNAP induced inhibition
of acetic acid induced abdominal stretching in chronic morphine treated
mice. These findings suggest that BNAP is a dual MOR antagonist/KOR
agonist and may have functional use in irritable bowel patients
Design, Synthesis, and Biological Evaluation of 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan Derivatives as Peripheral Selective μ Opioid Receptor Agents
Peripheral selective μ opioid receptor (MOR) antagonists
could alleviate the symptoms of opioid-induced constipation (OIC)
without compromising the analgesic effect of opioids. However, a variety
of adverse effects were associated with them, partially due to their
relatively low MOR selectivity. NAP, a 6β-<i>N</i>-4′-pyridyl substituted naltrexamine derivative, was identified
previously as a potent and highly selective MOR antagonist mainly
acting within the peripheral nervous system. The noticeable diarrhea
associated with it prompted the design and synthesis of its analogues
in order to study its structure–activity relationship. Among
them, compound <b>8</b> showed improved pharmacological profiles
compared to the original lead, acting mainly at peripheral while increasing
the intestinal motility in morphine-pelleted mice (ED<sub>50</sub> = 0.03 mg/kg). The slight decrease of the ED<sub>50</sub> compared
to the original lead was well compensated by the unobserved adverse
effect. Hence, this compound seems to be a more promising lead to
develop novel therapeutic agents toward OIC