Discovery of Biased Mu‐Opioid Receptor Agonists for the Treatment of Pain

Abstract

G protein‐biased mu‐opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities in vivo and greater bias toward G protein signaling in vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i ((S)‐1‐(3‐(benzo[d][1,3]dioxol‐4‐yl)‐2‐(dimethylamino)propyl)‐3‐phenethylurea) and 7 j ((S)‐1‐(3‐(benzo[d][1,3]dioxol‐4‐yl)‐2‐(dimethylamino)propyl)‐3‐benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less β‐arrestin‐2 recruitment.

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

“…After intrathecal administration, PZM21 mimicked morphine, producing naltrexone sensitive antiallodynic effects associated with long-lasting scratching [ 58 ]. The chemical template of PZM21 has been used for structure activity relationship studies that led to the identification of novel G-protein-biased mu-receptor agonists [ 59 , 60 ].…”

Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

“…1 H NMR (800 MHz, CDCl 3 ): δ 11.55 (s, 1H), 10.23 (s, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.35−7.30 (m, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.77 (s, 1H), 6.05 (s, 1H), 3.81 (s, 2H), 2.44 (q, J = 7.5 Hz, 2H), 2.26 (s, 3H), 1.24 (t, J = 7.4 Hz, 3H). 13 (36). Prepared using general procedure A using 2-(m-tolyl)acetic acid (0.045 g, 0.30 mmol, 1.3 equiv), BTFFH (0.11 g, 0.34 mmol, 1.5 equiv), DCM (0.5 mL), DIPEA (180 μL, 1.0 mmol, 4.3 equiv), and 5 (0.050 g, 0.23 mmol, 1 equiv).…”

“…35 One potential approach under investigation to limit these side effects is the development of biased MOR agonists that favor signaling through the G protein pathway and reduce the βarrestin pathway signal. 36 Alternatively, our group and others have shown that it is possible to target the activity of the downstream AC directly, bypassing the MOR entirely. 37−39 This strategy would allow for effective inhibition of chronic pain through AC inhibition, while avoiding negative side effects induced by clinically used MOR agonists, thus increasing the therapeutic index.…”

“…Additionally, chronic opioid administration leads to compensatory neuroadaptation, including upregulation of AC1 to offset the reduced cAMP signal and ultimately leading to tolerance and dependence. ,, Moreover, activation of the MOR signaling pathway has several undesired side effects, some of which are mediated by recruitment of β-arrestins and the release of Gβγ, which can lead to the development of physiological tolerance and may also contribute to opioid-induced respiratory depression, respectively. − Furthermore, MOR expression is not limited to the brain but is also expressed peripherally, leading to other common side effects such as opioid-induced constipation . One potential approach under investigation to limit these side effects is the development of biased MOR agonists that favor signaling through the G protein pathway and reduce the β-arrestin pathway signal . Alternatively, our group and others have shown that it is possible to target the activity of the downstream AC directly, bypassing the MOR entirely. − This strategy would allow for effective inhibition of chronic pain through AC inhibition, while avoiding negative side effects induced by clinically used MOR agonists, thus increasing the therapeutic index.…”

Into the Fray! A Beginner's Guide to Medicinal Chemistry

“…[142,143] However, given that the majority of clinically efficacious opioid analgesics require interaction with the MOR, there is still substantial interest in developing μ-agonists with reduced side effects. [144] From a physiological viewpoint, pain is often associated with acidosis of the injured tissue. [145] Classical SAR data has shown that for efficient interaction with the MOR, compounds must preferentially feature a protonatable tertiary amine.…”