4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ₁ Receptor Antagonists for the Treatment of Pain

Abstract

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ 1 R) and the μopioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ 1 R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ 1 R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ 1 R antagonism may be a useful strategy for obtaining potent and safer analgesics.

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

“…A very successful med-chem programme focused on dual µOR agonists/σ 1 R antagonists was recently described by García et al (of ESTEVE Pharmaceuticals SA) [111,112].…”

“…The initial compounds were designed as a result of merging 3D-pharmacophore models of both receptors (based on morphine for µOR and based on a model by Laggner et al [113] as well as on the in-house SAR data [114] in the case of σ 1 R). S5 for structures and affinities) were reported to have been obtained and tested [111,112], out of which about a half exhibited K i < 100 nM for MOR and about 50 of them showed K i < 100 nM for σ 1 R. Many examples had singledigit nanomolar K i 's either for one of the receptors or for both. The issues that were mainly fought with during the SAR exploration was the propensity of these structures to interact with hERG channels and α 1A -adrenergic receptors (α 1A R; associated with cardiac toxicity).…”

Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

“…Based on this model, several compounds were synthesized, and the 4-aryl-1-oxa-4,9diazaspiro [5.5]undecane derivative 13 (Figure 13) provided the best results on both targets. (13)(14)(15)(16) and their K i and IC 50 values for σ 1 (σ 1 R), µ-opioid (MOR) and alpha-1 adrenergic (α 1 AR) receptors and human ether-a-go-go-related gene channel (hERG) [139,140].…”

“…administration. Moreover, local administration of the compound provided promising results [139]. Further optimization of the compound was conducted with the production of new dual ligands with enhanced activity.…”

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

“…Working in the paradigm of multi-functional analgesics, researchers have investigated molecules designed by joining pharmacophores of various molecular targets and functional activities. The considered combinations are as diverse as MOR agonist/DOR agonist [6,7] MOR agonist/DOR antagonist [8,9], MOR agonist/cholecystokinin CCK2 receptor antagonist [10,11], MOR agonist/ neurotensin agonist [12,13], MOR agonist/ melanocortin-4 antagonist [14], MOR agonist/σ1-receptor antagonist [15,16], MOR agonist/voltage gated calcium channel (VGCC) blocker [17], MOR agonist/cannabinoid-1 receptors agonist [18] or MOR agonist/neuropeptide FF receptor agonist [19].…”