A Tale of Switched Functions: From Cyclooxygenase Inhibition to M-Channel Modulation in New Diphenylamine Derivatives

Cyclooxygenase (COX) enzymes are molecular targets of nonsteroidal anti-inflammatory drugs (NSAIDs), the most used medication worldwide. However, the COX enzymes are not the sole molecular targets of NSAIDs. Recently, we showed that two NSAIDs, diclofenac and meclofenamate, also act as openers of Kv7.2/3 K+ channels underlying the neuronal M-current. Here we designed new derivatives of diphenylamine carboxylate to dissociate the M-channel opener property from COX inhibition. The carboxylate moiety was derivatized into amides or esters and linked to various alkyl and ether chains. Powerful M-channel openers were generated, provided that the diphenylamine moiety and a terminal hydroxyl group are preserved. In transfected CHO cells, they activated recombinant Kv7.2/3 K+ channels, causing a hyperpolarizing shift of current activation as measured by whole-cell patch-clamp recording. In sensory dorsal root ganglion and hippocampal neurons, the openers hyperpolarized the membrane potential and robustly depressed evoked spike discharges. They also decreased hippocampal glutamate and GABA release by reducing the frequency of spontaneous excitatory and inhibitory post-synaptic currents. In vivo, the openers exhibited anti-convulsant activity, as measured in mice by the maximal electroshock seizure model. Conversion of the carboxylate function into amide abolished COX inhibition but preserved M-channel modulation. Remarkably, the very same template let us generating potent M-channel blockers. Our results reveal a new and crucial determinant of NSAID-mediated COX inhibition. They also provide a structural framework for designing novel M-channel modulators, including openers and blockers

Association between progesterone treatment and neonatal outcome in preterm births: a retrospective analysis

This retrospective study was conducted to determine if infants born prematurely despite prophylactic maternal progesterone treatment during pregnancy may still benefit from its adjunct properties and have decreased neonatal complications. 248 women treated with vaginal/intramuscular progesterone during pregnancy and 2519 controls who gave birth to a preterm newborn (24 + 0–36 + 6 gestational weeks) at a tertiary medical centre in 2012–2019. The primary outcome measure was neonatal infectious composite outcome. Secondary outcome measures were other maternal and neonatal complications. Compared to controls, the study group was characterised by lower gestational age at birth (35.0 ± 2.66 vs. 36.0 ± 2.23 weeks, p < .001), lower birth weight (2294 vs. 2485 g, p < .001), higher rates of neonatal infectious composite outcome (27.82 vs. 21.36%, p = 0.024), NICU admission, periventricular leukomalacia, and mechanical ventilation. The higher neonatal infectious composite outcome is likely associated with the lower gestational age at birth in this high-risk group and not the progesterone treatment per se.IMPACT STATEMENT What is already known on this subject? Several randomised controlled trials have shown that progesterone administration in pregnancy significantly reduced the rate and complications of preterm birth. A recent study reported that vaginal administration of progesterone during pregnancy was more effective than intramuscular administration in decreasing vaginal group B Streptococcus (GBS) colonisation. This finding raises the question of whether progesterone treatment may have additional benefits besides preventing preterm birth and may reduce neonatal complication rate in preterm infants. What do the results of this study add? This is the first study examining the impact of gestational progesterone exposure on outcomes of preterm infants. The primary objective was a composite measure of infectious neonatal outcomes. Newborns who had progesterone exposure on average had lower gestational age, lower birth weight and higher neonatal infectious composite outcome. The significant difference is explained by lower gestational age. What are the implications of these findings for clinical practice and/or further research? Progesterone is widely used to prevent preterm birth, and may have important additive effects even when prematurity is not avoided. Although the findings did not support our initial hypothesis, they warrant further examination with larger cohorts