pKa of opioid ligands as a discriminating factor for side effects

Abstract

The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived μ-opioid receptor (MOR) agonists with reduced acid dissociation constants (pKa) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pKa, MOR affinity and [35S]-GTPγS binding at low and physiological pH values. In vivo, FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pKa values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand’s pKa value may be used as discriminating factor to design safer analgesics.

Opioid Receptors and Protonation-Coupled Binding of Opioid Drugs

“…Low extracellular pH might enhance inhibition of calcium ion channels by endorphin and morphine (Figure 1) [78]. The pKa of opioid drugs is typically above 7.5 [79,80], i.e., opioid drugs are positively charged at both physiological pH, as well as low pH typical for inflammation. The fluorinated fentanyl derivative NFEPP (Figure 5m) has a pKa of 6.82-which is significantly lower than the pKa of 8.43 for fentanyl [16].…”

“…Contrary to fentanyl, NFEPP appears to lack inhibition of peristalsis as a side effect [82]. Overall, the safety profile of fluorinated fentanyl derivatives, including NFEPP [79], depends on the pKa value of the drug, with lower pKa being associated with fewer side effects.…”

Amelioration of injury-induced tissue acidosis by a nonsteroidal analgesic attenuates antinociceptive effects of the pH-dependent opioid agonist NFEPP

“…Therefore, it was first necessary to verify that DCF was able to effectively reduce inflammation and local acidosis. The importance of this aspect is illustrated by the peculiar pharmacodynamics of NFEPP: its functional restriction to opioid receptors expressed in peripheral inflamed tissue is due to its reduced pK a (6.8) and consequently to its selective protonation in acidotic environments 11 , 13 . In contrast, the conventional opioid fentanyl has a pK a value of 8.4 17 and is therefore protonated at both normal and acidotic pH values.…”

“…injection of CFA (150 µl) into the right hindpaw under brief isoflurane anesthesia. Behavioral tests were performed 4 days after CFA administration, as described previously 2 , 11 , 12 , 14 .…”

Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent agonist NFEPP

“…Recently, our group designed a new MOR agonist, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-Nphenyl propionamide (NFEPP), with a lower acid dissociation constant (pK a ) (Spahn et al, 2017;Rosas et al, 2019;Lešnik et al, 2020;Ray et al, 2020). NFEPP selectively activated peripheral MORs in inflamed tissues at low pH values (common in most painful injuries) whereas a conventional opioid (fentanyl) was equally active at both low and normal pH values (Spahn et al, 2017;Rodriguez-Gaztelumendi et al, 2018;Stein, 2018;Del Vecchio et al, 2019;Jiménez-Vargas et al, 2022). Targeting opioid receptors in the PNS at the site of injury avoids CNS side effects, while still contributing to strong analgesia, as previously demonstrated in preclinical and clinical studies: (i) locally applied opioids relieve severe clinical pain and a large proportion of the analgesic effects of systemically administered opioids is mediated by opioid receptors in the PNS (Jagla et al, 2014;Machelska and Celik, 2018;Martínez and Abalo, 2020); (ii) input from peripheral sensory neurons is essential in numerous pain syndromes (Berta et al, 2017;Sexton et al, 2018); (iii) upon injury, MOR expression is upregulated in peripheral sensory neurons and the perineurial barrier is disrupted, eventually increasing accessibility of the drugs' target (reviewed in Machelska and Celik, 2018;Jeske, 2019).…”