Multiple Mechanisms Underlying the Long Duration of Action of Thienorphine, A Novel Partial Opioid Agonist for the Treatment of Addiction

Abstract

These results indicate that multiple factors, including persistent receptor occupation and enhanced receptor downregulation, may contribute to the long-lasting effects of thienorphine that would be beneficial for its application in addiction treatment.

Insights into the mechanisms underlying opioid use disorder and potential treatment strategies

“…The primary mechanisms underlying the inhibitory effect of agmatine on opioid use disorder and relapse involve ① the acceleration of opioid-induced μ receptor trafficking, recycling and resensitization, ② a reduction in dopamine release via enhancement of negative feedback modulation by dynorphinand ③ modulation of glutamate neurotransmissions. DA, dopamine; GRK, GPCR kinases long-lasting effects of thienorphine (Yu et al, 2014). Given that the abused opioid is unable to activate enough μ receptor to produce an abuse-related effect when a sufficient number (>80%) of μ receptor are occupied (Greenwald et al, 2014), thienorphine-induced decrease in unoccupied μ receptor reserves would be beneficial for its application as a candidate therapeutic for opioid use disorder.…”

“…Thienorphine, a chemically new opioid and buprenorphine analogue, was developed at our institute. Competitive receptor binding and [ 35 S]GTPγS binding assays have shown that thienorphine is a potent non‐selective partial agonist at μ and κ receptors (J. X. Li et al, 2007; Yu, Li, et al, 2014; Yu, Yue, et al, 2006). Compared with buprenorphine, thienorphine exhibits higher binding affinity for μ receptor, higher antinociceptive and a longer duration of action (long‐lasting effects), along with better oral bioavailability (Yu, Li, et al, 2014; Yu, Yue, et al, 2006).…”

“…Competitive receptor binding and [ 35 S]GTPγS binding assays have shown that thienorphine is a potent non‐selective partial agonist at μ and κ receptors (J. X. Li et al, 2007; Yu, Li, et al, 2014; Yu, Yue, et al, 2006). Compared with buprenorphine, thienorphine exhibits higher binding affinity for μ receptor, higher antinociceptive and a longer duration of action (long‐lasting effects), along with better oral bioavailability (Yu, Li, et al, 2014; Yu, Yue, et al, 2006). Like buprenorphine, sustained thienorphine causes much lower naloxone‐challenged withdrawal signs than those induced by chronic morphine administration (Zhou et al, 2020).…”

“…The effect of thienorphine against morphine‐induced lethality in mice is stronger than that of buprenorphine. The duration of the antinociceptive effect of thienorphine is similar to that of buprenorphine, but its antagonism of morphine‐induced lethality (more than 15 days) is much longer lasting than that of buprenorphine (Yu, Li, et al, 2014; Yu, Yue, et al, 2006). Thienorphine‐loaded poly(lactic‐ co ‐glycolic acid), PLGA, microspheres are being developed to further extend the duration of action of thienorphine to approximately 28 days in rats and 25 days in beagle dogs (Yang et al, 2013; Yang & Gao, 2010).…”

Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate

“…Thienorphine (TNP), N-Cyclopropylmehtyl-7α-[(R)-1-hydroxyl-1-methyl-3-(thien-2-yl)propyl]-6, 14-endoethanotetrahydronooripavine, was synthesized as a ramification of buprenorphine, and identified to be a novel non-selective opioid partial agonist (Liu et al, 2005 ; Yu et al, 2006 ). When compared with buprenorphine, TNP showed high binding affinity with the μ-opioid receptor in vitro and a better oral bioavailability in vivo (Li et al, 2007 ; Yu et al, 2013 ). TNP was developed for the treatment of opioid dependence.…”