Self-immolative dendrimers disassemble through a domino-like chain fragmentation initiated by a single cleavage at the dendrimer core. We have designed and synthesized dendritic molecules that resemble dendritic architectures present in nature. The unique design allows a cleavage signal received by any one of the multiple triggers on one side of the dendrimer to be transferred convergently to a focal point. The signal is divergently amplified through to the other side of the dendrimer, reporter units are released, and fluorescence is emitted. During signal propagation, the dendritic molecule disassembles in a self-immolative manner into small fragments. These compounds are the longest dendritic system ever reported to disassemble through sequential self-immolative reactions. The synthesized dendritic molecules have an architecture and signal-conducting activity related to that of neurons.
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.
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