The voltage-gated potassium channels of the KV7 family (KV7.1–5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2–5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2–5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.
References
[1]
Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, et al. (1998) KCNQ2 and KCNQ3 Potassium Channel Subunits: Molecular Correlates of the M-Channel. Science 282: 1890–1893. doi: 10.1126/science.282.5395.1890
[2]
Jentsch TJ (2000) Neuronal KCNQ potassium channels:physislogy and role in disease. Nat Rev Neurosci 1: 21–30.
[3]
Brown DA, Adams PR (1980) Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature 283: 673–676. doi: 10.1038/283673a0
[4]
Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, et al. (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 18: 25–29. doi: 10.1038/ng0198-25
[5]
Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, et al. (1998) A Potassium Channel Mutation in Neonatal Human Epilepsy. Science 279: 403–406. doi: 10.1126/science.279.5349.403
[6]
Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, et al. (1998) A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 18: 53–55. doi: 10.1038/ng0198-53
[7]
Blackburn-Munro G, Jensen BS (2003) The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain. Eur J Pharmacol 460: 109–116. doi: 10.1016/s0014-2999(02)02924-2
[8]
Wu YJ, Boissard CG, Greco C, Gribkoff VK, Harden DG, et al. (2003) (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide: An Orally Bioavailable KCNQ2 Opener with Significant Activity in a Cortical Spreading Depression Model of Migraine. J Med Chem 46: 3197–3200. doi: 10.1021/jm034073f
[9]
Hansen HH, Ebbesen C, Mathiesen C, Weikop P, Ronn LC, et al. (2006) The KCNQ Channel Opener Retigabine Inhibits the Activity of Mesencephalic Dopaminergic Systems of the Rat. J Pharmacol Exp Ther 318: 1006–1019. doi: 10.1124/jpet.106.106757
[10]
Korsgaard MPG, Hartz BP, Brown WD, Ahring PK, Strobaek D, et al. (2005) Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal Kv7 Channels. J Pharmacol Exp Ther 314: 282–292. doi: 10.1124/jpet.105.083923
[11]
Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H (2005) The New Anticonvulsant Retigabine Favors Voltage-Dependent Opening of the Kv7.2 (KCNQ2) Channel by Binding to Its Activation Gate. Mol Pharmacol 67: 1009–1017. doi: 10.1124/mol.104.010793
[12]
Schenzer A, Friedrich T, Pusch M, Saftig P, Jentsch TJ, et al. (2005) Molecular Determinants of KCNQ (Kv7) K+ Channel Sensitivity to the Anticonvulsant Retigabine. J Neurosci 25: 5051–5060. doi: 10.1523/jneurosci.0128-05.2005
[13]
Bentzen BH, Schmitt N, Calloe K, Dalby-Brown W, Grunnet M, et al. (2006) The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. Neuropharmacology 51: 1068–1077. doi: 10.1016/j.neuropharm.2006.07.001
[14]
Blom SM, Schmitt N, Jensen HS (2009) The acrylamide (S)-2 as a positive and negative modulator of Kv7 channels expressed in Xenopus laevis oocytes. PLoS ONE 4: e8251. doi: 10.1371/journal.pone.0008251
[15]
Xiong Q, Sun H, Zhang Y, Nan F, Li M (2008) Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers. Proc Natl Acad Sci U S A 105: 3128–3133. doi: 10.1073/pnas.0712256105
[16]
Padilla K, Wickenden AD, Gerlach AC, McCormack K (2009) The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site. Neurosci Lett 465: 138–142. doi: 10.1016/j.neulet.2009.08.071
[17]
Blom SM, Schmitt N, Jensen HS (2010) Differential effects of ICA-27243 on cloned K(V)7 channels. Pharmacology 86: 174–181. doi: 10.1159/000317525
[18]
Miceli F, Soldovieri MV, Martire M, Taglialatela M (2008) Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs. Curr Opin Pharmacol 8: 65–74. doi: 10.1016/j.coph.2007.10.003
[19]
Lange W, Geissendorfer J, Schenzer A, Grotzinger J, Seebohm G, et al. (2009) Refinement of the Binding Site and Mode of Action of the Anticonvulsant Retigabine on KCNQ K+ Channels. Mol Pharmacol 75: 272–280. doi: 10.1124/mol.108.052282
[20]
Wu YJ, He H, Sun LQ, L'Heureux A, Chen J, et al. (2004) Synthesis and Structure-Activity Relationship of Acrylamides as KCNQ2 Potassium Channel Openers. J Med Chem 47: 2887–2896. doi: 10.1021/jm0305826
[21]
Risgaard R, Ettrup A, Balle T, Dyssegaard A, Hansen HD, et al. (2013) Radiolabelling and PET brain imaging of the α1-adrenoceptor antagonist Lu AE43936. Nuclear medicine and biology 40: 135–140. doi: 10.1016/j.nucmedbio.2012.09.010
[22]
Redrobe JP, Elster L, Frederiksen K, Bundgaard C, Jong IEM, et al. (2011) Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats. Psychopharmacology 221: 451–468. doi: 10.1007/s00213-011-2593-9
[23]
Wu YJ, Boissard CG, Chen J, Fitzpatrick W, Gao Q, et al. (2004) (S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydr？o-2H-benzo[and ]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)？-acrylamideis a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons. Bioorg Med Chem Lett 14: 1991–1995. doi: 10.1002/chin.200431132
[24]
Talebizadeh Z, Kelley PM, Askew JW, Beisel KW, Smith SD (1999) Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat 14: 493–501. doi: 10.1002/(sici)1098-1004(199912)14:6<493::aid-humu8>3.0.co;2-p
[25]
Gribkoff VK (2008) The therapeutic potential of neuronal KV7 (KCNQ) channel modulators: an update. Expert Opin Ther Tar 12: 565–581. doi: 10.1517/14728222.12.5.565
Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1: 133–152. doi: 10.1002/syn.890010203
[28]
Duncan GE, Sheitman BB, Lieberman JA (1999) An integrated view of pathophysiological models of schizophrenia. Brain Res Brain Res Rev 29: 250–264. doi: 10.1016/s0165-0173(99)00002-8
[29]
Lieberman JA, Kane JM, Alvir J (1987) Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 91: 415–433. doi: 10.1007/bf00216006
[30]
Nickolson VJ, Tam SW, Myers MJ, Cook L (1990) Du P 996 (3,3-Bis(4-Pyrindinylmethyl)-1 -Phenylindolin-2-One) Enhances the StimuIus induced Release of Acetylcholine From Rat Brain In Vitro and In Vivo. Drug Dev Res 19: 285–300. doi: 10.1002/ddr.430190307
[31]
Cook L, Nickolson VJ, Steinfels GF, Rohrbach KW, Denoble VJ (1990) Cognition enhancement by the acetylcholine releaser DuP 996. Drug Dev Res 19: 301–314. doi: 10.1002/ddr.430190308
[32]
Aiken SP, Lampe BJ, Murphy PA, Brown BS (1995) Reduction of spike frequency adaptation and blockade of M-current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer. Br J Pharmacol 115: 1163–1168. doi: 10.1111/j.1476-5381.1995.tb15019.x
[33]
S？gaard R, Ljungstr？m T, Pedersen KA, Olesen SP, Jensen BS (2001) KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Am J Physiol Cell Physiol 280: C859–866.
[34]
Sotty F, Damgaard T, Montezinho LP, Mork A, Olsen CK, et al. (2009) Antipsychotic-like effect of retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl？)carbamicacid ester], a KCNQ potassium channel opener, via modulation of mesolimbic dopaminergic neurotransmission. J Pharmacol Exp Ther 328: 951–962. doi: 10.1124/jpet.108.146944
[35]
Hansen HH, Andreasen JT, Weikop P, Mirza N, Scheel-Kruger J, et al. (2007) The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine. Eur J Pharmacol 570: 77–88. doi: 10.1016/j.ejphar.2007.05.029
[36]
Hansen HH, Waroux O, Seutin V, Jentsch TJ, Aznar S, et al. (2008) Kv7 channels: interaction with dopaminergic and serotonergic neurotransmission in the CNS. J Physiol 586: 1823–1832. doi: 10.1113/jphysiol.2007.149450
[37]
Mackie AR, Byron KL (2008) Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention. Molecular Pharmacology 74: 1171–1179. doi: 10.1124/mol.108.049825
[38]
Greenwood IA, Ohya S (2009) New tricks for old dogs: KCNQ expression and role in smooth muscle. British Journal of Pharmacology 156: 1196–1203. doi: 10.1111/j.1476-5381.2009.00131.x
[39]
Stott JB, Jepps TA, Greenwood IA (2013) Kv7 potassium channels: a new therapeutic target in smooth muscle disorders. Drug Discov Today.
[40]
Chadha PS, Jepps TA, Carr G, Stott JB, Zhu H-L, et al. (2014) Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide-Induced Cerebral Reactivity. Arteriosclerosis, Thrombosis, and Vascular Biology 34: 887–893. doi: 10.1161/atvbaha.114.303405
[41]
Khanamiri S, Soltysinska E, Jepps TA, Bentzen BH, Chadha PS, et al. (2013) Contribution of Kv7 Channels to Basal Coronary Flow and Active Response to Ischemia. Hypertension 62: 1090–1097. doi: 10.1161/hypertensionaha.113.01244
[42]
Chadha PS, Zunke F, Zhu H-L, Davis AJ, Jepps TA, et al. (2012) Reduced KCNQ4-Encoded Voltage-Dependent Potassium Channel Activity Underlies Impaired β-Adrenoceptor-Mediated Relaxation of Renal Arteries in Hypertension. Hypertension 59: 877–884. doi: 10.1161/hypertensionaha.111.187427
