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

Abstract

A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′-and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6’-nitro group varied significantly in the different “address” domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.

Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys

“…A second implication of the present study was that fentanyl/naltrexone mixtures could be used to stratify MOR ligands based on their in vivo antinociceptive efficacy in rhesus monkeys. In the present study, NAQ produced ,10%MPE and these results are consistent with and extend previous findings in mice (Zhang et al, 2014;Yuan et al, 2015) and rats (Siemian et al, 2016). Buprenorphine (Walker et al, 1995;Maguire and France, 2014), nalbuphine (Walker et al, 1993;France and Gerak, 1994;Banks et al, 2010b), morphine (Bowen et al, 2002), oxycodone, and methadone (Stevenson et al, 2003;Banks et al, 2010b) produced dose-dependent and thermal intensity-dependent antinociception in the present study, and these results were generally consistent with the extant literature examining MOR agonists in a warm-water tail-withdrawal procedure in monkeys.…”

“…Buprenorphine (Walker et al, 1995;Maguire and France, 2014), nalbuphine (Walker et al, 1993;France and Gerak, 1994;Banks et al, 2010b), morphine (Bowen et al, 2002), oxycodone, and methadone (Stevenson et al, 2003;Banks et al, 2010b) produced dose-dependent and thermal intensity-dependent antinociception in the present study, and these results were generally consistent with the extant literature examining MOR agonists in a warm-water tail-withdrawal procedure in monkeys. With one major exception (see the results regarding nalbuphine in the next paragraph), the order of MOR efficacies for these drugs as ranked here agrees with the order of efficacies as determined by in vitro approaches such as agonist-stimulated GTPgS binding (Selley et al, 1998;Alt et al, 2001;Yuan et al, 2015). Specifically, both approaches yield a rank order of lowest-tohighest efficacy of naltrexone , NAQ , buprenorphine , morphine , oxycodone , fentanyl , methadone.…”

“…Following these initial fentanyl/naltrexone fixed-proportion experiments, three additional studies were conducted. First, for comparison with effects of the fentanyl/naltrexone mixtures, cumulative doseeffect functions were determined for a series of six other MOR ligands that varied from low to high in their efficacy at mu receptors as determined by in vitro assays of agonist-stimuluated GTPgS binding (Emmerson et al, 1996;Selley et al, 1998;Alt et al, 2001;Thompson et al, 2004;Yuan et al, 2015): 17-cyclopropylmethyl-3,14b-dihyroxy-4,5a-epoxy-6a-[(39-isoquinolyl)acetamindo]morphinan (NAQ) (0.1-10 mg/kg, i.m. ), buprenorphine (0.032-3.2 mg/kg, i.m.…”

“…The goal of the present study was to test the utility of this approach using the competitive MOR agonist fentanyl and antagonist naltrexone (Negus et al, 1993;Emmerson et al, 1994Emmerson et al, , 1996Walker et al, 1994). Effects of these drugs administered alone and in fixed-proportion mixtures were determined in an assay of thermal nociception using two thermal stimulus intensities (50 and 54°C warm water) and compared with effects produced by six other MOR ligands shown previously to vary in their relative MOR efficacies in in vitro assays of agonist-stimulated GTPgS binding (Emmerson et al, 1996;Selley et al, 1998;Alt et al, 2001;Thompson et al, 2004;Yuan et al, 2015). We predicted that the effects of fentanyl, naltrexone, and the mixtures would match the predicted results in Fig.…”

Characterization of 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN) as a Novel Opioid Receptor Modulator for Opioid Use Disorder Treatment

“…46–48 This could explain why the K e of NTX was not significantly different from its K i (NTX K i (nM) = 0.33 ± 0.02) (Table 1). 49 Thus, NAN acted as a high affinity MOR competitive antagonist in both mMOR-CHO cells and mouse thalamus. In addition, NAN concentration-dependently inhibited Ca 2+ flux induced by DAMGO in the Ca 2+ flux assay using G α qi5 transfected hMOR-CHO cells (Figure 4).…”