title: A tale of switched functions: from cyclooxygenase inhibition to M-channel modulation in new diphenylamine derivatives.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Peretz
authors.forename: Nurit
authors.initials: N
authors.lastname: Degani-Katzav
authors.forename: Maya
authors.initials: M
authors.lastname: Talmon
authors.forename: Eyal
authors.initials: E
authors.lastname: Danieli
authors.forename: Anna
authors.initials: A
authors.lastname: Gopin
authors.forename: Eti
authors.initials: E
authors.lastname: Malka
authors.forename: Rachel
authors.initials: R
authors.lastname: Nachman
authors.forename: Amiram
authors.initials: A
authors.lastname: Raz
authors.forename: Doron
authors.initials: D
authors.lastname: Shabat
authors.forename: Bernard
authors.initials: B
authors.lastname: Attali
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D004159:Diphenylamine / Q000494:pharmacology*; D008469:Meclofenamic Acid / Q000494:pharmacology; D051379:Mice; D015221:Potassium Channels / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D015221:Potassium Channels; D004008:Diclofenac; D008469:Meclofenamic Acid; D004159:Diphenylamine