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

Abstract

Peripheral selective mu 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-N-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 8 showed improved pharmacological profiles compared to the original lead, acting mainly at peripheral while increasing the intestinal motility in morphine-pelleted mice (ED50=0.03 mg/kg). The slight decrease of the ED50 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.

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

“…The competitive radioligand binding assays were performed as described previously. 36, 37 To compare with previous results as well as for consistency purpose, [ 3 H]naloxone (NLX), [ 3 H]naltrindole (NTI), and [ 3 H]diprenorphine (DPN) were used to label the MOR, DOR and KOR, respectively. The MOR [ 35 S]GTPγS binding assay was conducted to determine the efficacy of each ligand at the MOR as reported earlier.…”

“…36,37 Briefly, for the competition binding assay, [ 3 H]NLX, [ 3 H]DPN, and [ 3 H]NTI were used to label the MOR, the KOR, and the DOR, respectively. Aliquots of a membrane protein (30 µg) were incubated with the corresponding radioligand in the presence of different concentrations of the ligand under investigation in TME buffer (50 mM Tris, 3 mM MgCl 2 , 0.2 mM EGTA, pH 7.7) at 30 °C for 1.5 h. The bound radioactive ligand was separated from the free radioligand by filtration using the Brandel harvester (Biomedical Research & Development Laboratories, MD).…”

Design, Synthesis, and Biological Evaluation of 14-Heteroaromatic-Substituted Naltrexone Derivatives: Pharmacological Profile Switch from Mu Opioid Receptor Selectivity to Mu/Kappa Opioid Receptor Dual Selectivity

“…38, 39, 44 [ 3 H]naloxone (NLX), [ 3 H]naltrindole (NTI), and [ 3 H]norBNI (for compounds 2 – 9 ) or [ 3 H]diprenorphine (DPN, for compounds 10 – 20 ) were used to label the MOR, the DOR and the KOR, respectively. The MOR [ 35 S]-GTP γ S binding assay was conducted to determine whether each of the new ligands would act as a full agonist, a partial agonist, or an antagonist at the MOR as illustrated before.…”

Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function

“…3–5 Furthermore, naltrexone bound to the MOR and the kappa opioid receptor (KOR) with similar affinity. 6 Naltrexone also possessed moderate efficacy at the KOR, 7 which was proposed to counteract its therapeutic efficiency for addiction treatment. 8 …”