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A tale of switched functions: from cyclooxygenase inhibition to M-channel modulation in new diphenylamine derivatives.

Peretz A, Degani-Katzav N, Talmon M, Danieli E, Gopin A, Malka E, Nachman R, Raz A, Shabat D, Attali B - PLoS ONE (2007)

Bottom Line: They also decreased hippocampal glutamate and GABA release by reducing the frequency of spontaneous excitatory and inhibitory post-synaptic currents.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.

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.

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Pharmacophoric features of M-channels deduced from SAR studies of diphenylamine derivatives.
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pone-0001332-g002: Pharmacophoric features of M-channels deduced from SAR studies of diphenylamine derivatives.

Mentions: Considering the M-channel activity, several important features could be deduced from the structure-activity relation (SAR) study (Table 1, Table S1 and Figure 2). In contrast to the dramatic impact of the carboxylate conversion into amide on COX inhibition, the M-channel openers can clearly accommodate with carboxylate, ester and amide functionalities. Table 1 and Table S1 show that openers of the Kv7.2/3 channels are found in compounds bearing a carboxylate (e.g., compound 3, diclofenac, or meclofenamate), an ester group (e.g., compounds 8, 9 and 15) as well as an amide function (e.g., compounds 2, 6, 7 and 16). The opener activity is also displayed by derivatives bearing either ether or alkyl chains (e.g., compounds 4–7 and 2 or 8 and 9). As the main opener effect of the various compounds is to cause a hyperpolarizing shift of the activation curve of Kv7.2/3 channels, the extent of the left-shift (ΔV50) is a faithful measure of the opener potency (Table 1 and Table S1). Hence, we found that substituting the aromatic rings with NO2 groups significantly increased the left-shift in activation. In the ester series, compound 9 is a much weaker opener (ΔV50 = −4.1 mV) than compound 15 which bears one NO2 (ΔV50 = −31.0 mV). Similarly, in the amide series, compound 6 possessing three NO2 is a stronger opener (ΔV50 = −31.3 mV) than compound 7 which bears only one NO2 (ΔV50 = −12.2 mV).


A tale of switched functions: from cyclooxygenase inhibition to M-channel modulation in new diphenylamine derivatives.

Peretz A, Degani-Katzav N, Talmon M, Danieli E, Gopin A, Malka E, Nachman R, Raz A, Shabat D, Attali B - PLoS ONE (2007)

Pharmacophoric features of M-channels deduced from SAR studies of diphenylamine derivatives.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2131780&req=5

pone-0001332-g002: Pharmacophoric features of M-channels deduced from SAR studies of diphenylamine derivatives.
Mentions: Considering the M-channel activity, several important features could be deduced from the structure-activity relation (SAR) study (Table 1, Table S1 and Figure 2). In contrast to the dramatic impact of the carboxylate conversion into amide on COX inhibition, the M-channel openers can clearly accommodate with carboxylate, ester and amide functionalities. Table 1 and Table S1 show that openers of the Kv7.2/3 channels are found in compounds bearing a carboxylate (e.g., compound 3, diclofenac, or meclofenamate), an ester group (e.g., compounds 8, 9 and 15) as well as an amide function (e.g., compounds 2, 6, 7 and 16). The opener activity is also displayed by derivatives bearing either ether or alkyl chains (e.g., compounds 4–7 and 2 or 8 and 9). As the main opener effect of the various compounds is to cause a hyperpolarizing shift of the activation curve of Kv7.2/3 channels, the extent of the left-shift (ΔV50) is a faithful measure of the opener potency (Table 1 and Table S1). Hence, we found that substituting the aromatic rings with NO2 groups significantly increased the left-shift in activation. In the ester series, compound 9 is a much weaker opener (ΔV50 = −4.1 mV) than compound 15 which bears one NO2 (ΔV50 = −31.0 mV). Similarly, in the amide series, compound 6 possessing three NO2 is a stronger opener (ΔV50 = −31.3 mV) than compound 7 which bears only one NO2 (ΔV50 = −12.2 mV).

Bottom Line: They also decreased hippocampal glutamate and GABA release by reducing the frequency of spontaneous excitatory and inhibitory post-synaptic currents.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.

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.

Show MeSH
Related in: MedlinePlus