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

Abstract

The opioid crisis is a significant public health issue with more than 115 people dying from opioid overdose per day in the United States. The aim of the present study was to characterize the in vitro and in vivo pharmacological effects of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN), a μ opioid receptor (MOR) ligand that may be a potential candidate for opioid use disorder treatment that produces less withdrawal signs than naltrexone. The efficacy of NAN was compared to varying efficacy ligands at the MOR, and determined at the δ opioid receptor (DOR) and κ opioid receptor (KOR). NAN was identified as a low efficacy partial agonist for G-protein activation at the MOR and DOR, but had relatively high efficacy at the KOR. In contrast to high efficacy MOR agonists, NAN did not induce MOR internalization, downregulation, or desensitization, but it antagonized agonist-induced MOR internalization and stimulation of intracellular Ca2+ release. Opioid withdrawal studies conducted using morphine-pelleted mice demonstrated that NAN precipitated significantly less withdrawal signs than naltrexone at similar doses. Furthermore, NAN failed to produce fentanyl-like discriminative stimulus effects in rats up to doses that produced dose- and time-dependent antagonism of fentanyl. Overall, these results provide converging lines of evidence that NAN functions mainly as a MOR antagonist and support further consideration of NAN as a candidate medication for opioid use disorder treatment.

The rising crisis of illicit fentanyl use, overdose, and potential therapeutic strategies

“…The orexin-1 receptor antagonist SB-334867 was also shown to decrease motivation and demand for fentanyl in rats 136 . Therefore, these drugs could be considered candidates for the treatment of opioid use disorder 137 . Chronic anticonvulsant carbamazepine therapy was shown to increase fentanyl clearance and decrease plasma concentrations in neurosurgical patients, which may attenuate the actions of fentanyl 138 .…”

Opioid Ligands Addressing Unconventional Binding Sites and More Than One Opioid Receptor Subtype

“…[107,108] It was identified as a novel bitopic modulator. [108][109][110] After docking, molecular dynamics (MD) and several site-directed mutagenesis studies, the epoxymorphinan moiety of NAQ which is the "message" unit was found to bind with the μOR orthosteric site and the isoquinoline ring or the "address" unit to interact with the μOR allosteric site, resembling INTA. [109] Additionally, NAQ displayed a high binding affinity of 0.55 nM to μOR with over 200-fold selectivity over the δOR and 50-fold selectivity over the kOR.…”

“…[111][112][113][114][115][116][117][118] Pharmacokinetic studies verified that NAQ acted centrally. [110,145] A pharmacological study performed in rats showed that NAQ was able to significantly reverse the intracranial self-stimulation (ICSS) depression associated with morphine withdrawal. [111,119] Another derivative of INTA acting as a potent selective μOR antagonist both in vivo and in vitro is NAN (17-Cyclopropylmethyl-3,14β-dihydroxy-4,5a-epoxy-6α-(indole-7carboxamido)morphinan) (Scheme 8).…”

Computational Methods for Understanding the Selectivity and Signal Transduction Mechanism of Aminomethyl Tetrahydronaphthalene to Opioid Receptors

“…Additionally, opioid antagonists such as naloxone and naltrexone were used to treat opioid abuse, which did not have the side effects related to the MOR agonism. Some scientists make many efforts to develop newly selective MOR antagonists or μ/κ opioid receptor dual ligands for the treatment of opioid use disorder ( Figure 2 ) [ 17 , 18 , 19 ], and NFP could produce significantly fewer withdrawal symptoms than naloxone at similar doses in vivo.…”