A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models

Abstract

A novel mu-delta opioid agonist demonstrates enhanced efficacy with reduced tolerance and dependence in mouse neuropathic pain models.

N-Phenethyl Substitution in 14-Methoxy-N-methylmorphinan-6-ones Turns Selective µ Opioid Receptor Ligands into Dual µ/δ Opioid Receptor Agonists

“…This was not noticed for 14-OMO (3) vs. 3a, and 14-MM (4) vs. 4a, indicating that an increased µOR affinity can be achieved by either a 14-methoxy or by an N-phenethyl substitution, as key sites to be targeted in modulating the binding affinity and efficacy of morphinans to the µOR. Whereas replacement of the N-methyl substituent in morphine (1) and oxymorphone (2) by an N-phenethyl group enhanced binding affinity, selectivity and agonist potency at the µOR of 1a and 2a, the N-phenethyl substitution in 14-methoxy-N-methylmorphinan-6-ones (3 and 4) turned selective µOR ligands into dual µ/δOR agonists (3a and 4a), a profile that currently emerges as a promising approach to opioid analgesic drug discovery [26][27][28][29][30][31][32] . Furthermore, we have demonstrated that the N-phenethyl substituted morphinans 1a-4a are effective and potent antinociception agents without causing unwanted motor impairment in mice after s.c. administration.…”

“…Numerous pharmacological and biochemical reports and studies with opioid receptor knockout mice have provided evidence on the modulatory interactions between the µOR and δOR systems [22][23][24][25][26] . While the mechanisms are still unknown, several studies have established that the therapeutic profile of opioids could be improved by simultaneous modulation of the µOR and δOR, with compounds designed to target both receptors based on peptidic structures, non-peptidic structures or utilize the morphinan scaffold [25][26][27][28][29][30][31][32] . We 13 and others 11,12 have reported that the N-phenethyl substituted morphinans 1a and 2a exhibit increased antinociceptive potencies than their respective N-methyl analogues morphine (1) and oxymorphone (2) in mouse models of acute thermal nociception after subcutaneous (s.c.) administration, which is in line with findings from binding and functional in vitro assays.…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Clinically used opioid analgesics, such as morphine, oxycodone or fentanyl, are known to produce sedation and motor dysfunction, side effects that limits their clinical usefulness [33][34][35] . With literature evidence that mixed µOR/δOR agonists are efficacious analgesics with reduced side effects [25][26][27][28][29][30][31][32] , we have evaluated the effect of 3a and 4a as mixed µ/δOR agonists, and behavioral consequences of the replacement of the N-methyl group in N-methylmorphinans 1-4 by an N-phenethyl group in 1a-4a on motor coordination in mice using the rotarod assay, a well-established model for evaluating loss of coordinated locomotion 36 . The first behavioral data on motor function following systemic s.c. administration of N-phenethyl substituted derivatives of morphine and oxymorphone, 1a and 2a, respectively are presented.…”

Novel bifunctional hybrid compounds designed to enhance the effects of opioids and antagonize the pronociceptive effects of nonopioid peptides as potent analgesics in a rat model of neuropathic pain

“…These beneficial properties of the hybrids may be associated with DOP receptor activity because the effectiveness of DOP receptor ligands does not change in neuropathic pain. 33 , 40 , 42 , 70 In addition, a multimodal approach has been used in the treatment of neuropathic pain, 64 and SHU9119 causes a delay in the development of analgesic morphine tolerance, which is important for overcoming therapeutic restrictions. 26 , 59 , 62 Thus, the use of hybrids seems to be an interesting and promising direction for innovative therapies for the treatment of chronic pain.…”

Modulating β Arrestin-2 Recruitment at the δ- and μ-Opioid Receptors

“…[11][12][13][14] At present, no δOR-selective opioid agonists have been approved for clinical use, in part due to δOR agonists causing seizures, 15 a side effect that has been associated with β-Arr 2 recruitment. 16,17 Because of the described limitations associated with µOR-selective and δOR-selective opioids, a pharmacological strategy for treating acute and chronic pain has emerged that relies on dual activation of both the µOR and δOR, [18][19][20][21][22][23][24][25][26][27] and some of these bifunctional agonists indeed display antinociception with reduced tolerance, dependence, locomotor activation and selfadministration relative to classical morphinans. [18][19][20]27 Thus far, the development of these µOR/δOR dual agonists has largely ignored β-Arr 2 recruitment, which makes it impossible to correlate their reduced side effect profile with µOR/δOR dual agonism as opposed to β-Arr 2 recruitment.…”