Synthesis, molecular modeling, and pharmacological testing of bis-quinolinium cyclophanes: potent, non-peptidic blockers of the apamin-sensitive Ca(2+)-activated K(+) channel.

The synthesis and pharmacological testing of two series of novel bis-quinolinium cyclophanes as blockers of the apamin-sensitive Ca(2+)-activated K(+) (SK(Ca)) channel are presented. In these cyclophanes the two 4-aminoquinolinium groups are joined at the ring N atoms (linker L) and at the exocyclic N atoms (linker A). In those cases where A and L contain two or more aromatic rings each, the activity of the compound is not critically dependent upon the nature of the linkers. When A and L each have only one benzene ring, the blocking potency changes dramatically with simple structural variations in the linkers. One of these smaller cyclophanes having A = benzene-1,4-diylbis(methylene) and L = benzene-1, 3-diylbis(methylene) (3j, 6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1, 4)-dibenzenacyclodecaphanedium tritrifluoroacetate, UCL 1684) has an IC(50) of 3 nM and is the most potent non-peptidic SK(Ca) channel blocker described to date. Conformational analysis on the smaller cyclophanes using molecular modeling techniques suggests that the differences in the blocking potencies of the compounds may be attributable to their different conformational preferences.

[1]  H. Rochat,et al.  Characterization of PO1, a new peptide ligand of the apamin-sensitive Ca2+ activated K+ channel. , 2009, International journal of peptide and protein research.

[2]  P. M. Dunn.  UCL 1684: a potent blocker of Ca2+ -activated K+ channels in rat adrenal chromaffin cells in culture. , 1999, European journal of pharmacology.

[3]  W. H. Powell.  Phane nomenclature – I. Phane parent names (IUPAC Recommendations 1998) , 1998 .

[4]  D. Jenkinson,et al.  Bis-quinolinium Cyclophanes: A Novel Class of Potent Blockers of the Apamin-Sensitive Ca2+-Activated K+ Channel. , 1997 .

[5]  C. Ganellin,et al.  Synthesis, molecular modeling, and K+ channel-blocking activity of dequalinium analogues having semirigid linkers. , 1996, Journal of medicinal chemistry.

[6]  N. Marrion,et al.  Small-Conductance, Calcium-Activated Potassium Channels from Mammalian Brain , 1996, Science.

[7]  C. Ganellin,et al.  Synthesis and pharmacological testing of dequalinium analogues as blockers of the apamin-sensitive Ca(2+)-activated K+ channel: variation of the length of the alkylene chain. , 1996, Journal of Medicinal Chemistry.

[8]  P. Bougis,et al.  Characterization of a new peptide from Tityus serrulatus scorpion venom which is a ligand of the apamin‐binding site , 1996, FEBS letters.

[9]  C. Bourque,et al.  Activity dependence and functional role of the apamin‐sensitive K+ current in rat supraoptic neurones in vitro. , 1996, The Journal of physiology.

[10]  Ping Hx,et al.  Apamin-sensitive Ca2+-activated K+ channels regulate pacemaker activity in nigral dopamine neurons , 1996 .

[11]  D. Jenkinson,et al.  Discrimination between subtypes of apamin‐sensitive Ca2+‐ activated K+ channels by gallamine and a novel bis‐quaternary quinolinium cyclophane, UCL 1530 , 1996, British journal of pharmacology.

[12]  J. Brayden,et al.  Apamin‐sensitive K+ channels mediate an endothelium‐dependent hyperpolarization in rabbit mesenteric arteries. , 1995, The Journal of physiology.

[13]  H. Heller,et al.  Apamin, a selective SK potassium channel blocker, suppresses REM sleep without a compensatory rebound , 1995, Brain Research.

[14]  D. Galanakis,et al.  Synthesis and quantitative structure-activity relationships of dequalinium analogues as K+ channel blockers: investigation into the role of the substituent at position 4 of the quinoline ring. , 1995, Journal of medicinal chemistry.

[15]  C. Destrade,et al.  Post-test apamin injection suppresses a Kamin-like effect following a learning session in mice. , 1995, Neuroreport.

[16]  D. Jenkinson,et al.  Synthesis and qsar of dequalinium analogues AS K+ channel blockers. investigations on the role of the 4-amino group , 1995 .

[17]  D. Jenkinson,et al.  Synthesis and structure-activity relationships of dequalinium analogues as K+ channel blockers. Investigations on the role of the charged heterocycle. , 1995, Journal of medicinal chemistry.

[18]  M. Behrens,et al.  Possible role of apamin‐sensitive K+ channels in myotonic dystrophy , 1994, Muscle & nerve.

[19]  P. Strong,et al.  Comparable 30-kDa apamin binding polypeptides may fulfill equivalent roles within putative subtypes of small conductance Ca(2+)-activated K+ channels. , 1994, The Journal of biological chemistry.

[20]  P. M. Dunn.  Dequalinium, a selective blocker of the slow afterhyperpolarization in rat sympathetic neurones in culture. , 1994, European journal of pharmacology.

[21]  Mark S. Gordon,et al.  General atomic and molecular electronic structure system , 1993, J. Comput. Chem..

[22]  D. Jenkinson,et al.  Dequalinium: a potent inhibitor of apamin-sensitive K+ channels in hepatocytes and of nicotinic responses in skeletal muscle. , 1993, European journal of pharmacology.

[23]  H. Rochat,et al.  Characterization of a new leiurotoxin I‐like scorpion toxin , 1993, FEBS letters.

[24]  M. Behrens,et al.  Increase of apamin receptors in skeletal muscle induced by colchicine: possible role in myotonia. , 1992, The American journal of physiology.

[25]  S. David Morley,et al.  COSMIC(90): An improved molecular mechanics treatment of hydrocarbons and conjugated systems , 1991, J. Comput. Aided Mol. Des..

[26]  B. Bontempi,et al.  Effect of apamin, a toxin that inhibits Ca2+-dependent K+ channels, on learning and memory processes , 1991, Brain Research.

[27]  L. Strekowski,,et al.  Quantitative structure-activity relationship analysis of cation-substituted polyaromatic compounds as potentiators (amplifiers) of bleomycin-mediated degradation of DNA. , 1991, Journal of medicinal chemistry.

[28]  D. Robertson,et al.  Potassium channel modulators: scientific applications and therapeutic promise. , 1990, Journal of medicinal chemistry.

[29]  J. G. Vinter,et al.  Strategic approaches to drug design. I. An integrated software framework for molecular modelling , 1987, J. Comput. Aided Mol. Des..

[30]  G. Serratrice,et al.  Expression of apamin receptor in muscles of patients with myotonic muscular dystrophy , 1986, Nature.

[31]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[32]  M. Lazdunski,et al.  The presence in pig brain of an endogenous equivalent of apamin, the bee venom peptide that specifically blocks Ca2+-dependent K+ channels. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[33]  M. Lazdunski,et al.  Apamin, a neurotoxin specific for one class of Ca2+-dependent K+ channels. , 1983, Cell calcium.

[34]  R. Harris,et al.  Calcium-dependent 86 Rb efflux and ethanol intoxication: studies of human red blood cells and rodent brain synaptosomes. , 1983, European journal of pharmacology.

[35]  D. Jenkinson,et al.  Effects of quinine and apamin on the calcium‐dependent potassium permeability of mammalian hepatocytes and red cells. , 1981, The Journal of physiology.

[36]  D. Jenkinson,et al.  Apamin blocks certain neurotransmitter-induced increases in potassium permeability , 1979, Nature.

[37]  W. Wenner.  BIS(BROMOMETHYL) COMPOUNDS , 1952 .

[38]  D. Cram,et al.  Macro Rings. I. Preparation and Spectra of the Paracyclophanes , 1951 .

[39]  D. Jenkinson,et al.  Bis-quinolinium cyclophanes: 6,10-diaza-3(1,3),8(1,4)-dibenzena-1,5(1,4)- diquinolinacyclodecaphane (UCL 1684), the first nanomolar, non-peptidic blocker of the apamin-sensitive Ca(2+)-activated K+ channel. , 1998, Journal of medicinal chemistry.

[40]  INTERNATIONAL UNION OF PURE AND APPLIED CHEMISTRY ORGANIC CHEMISTRY DIVISION COMMISSION ON NOMENCLATURE OF ORGANIC CHEMISTRY* PHANE NOMENCLATURE PART I: PHANE PARENT NAMES , 1998 .

[41]  G. Kaczorowski,et al.  Pharmacology of Potassium Channels , 1997, Advances in pharmacology.

[42]  D. Jenkinson,et al.  On the Concept of a Bivalent Pharmacophore for SKCa Channel Blockers: Synthesis, Pharmacological Testing, and Radioligand Binding Studies on Mono‐, Bis‐, and Tris‐quinolinium Compounds , 1996, Archiv der Pharmazie.

[43]  C. Ganellin,et al.  Synthesis and quantitative structure-activity relationship of a novel series of small conductance Ca(2+)-activated K+ channel blockers related to dequalinium. , 1996, Journal of medicinal chemistry.

[44]  T. Shibasaki,et al.  Endothelin ETA and ETB receptors mediate endothelin-1-induced apamin-sensitive relaxation in the guinea pig ileum. , 1996, Japanese journal of pharmacology.

[45]  M. Lazdunski,et al.  Characterization and partial purification from pheochromocytoma cells of an endogenous equivalent of scyllatoxin, a scorpion toxin which blocks small conductance Ca(2+)-activated K+ channels. , 1992, Brain Research.

[46]  P. Strong.  Potassium channel toxins. , 1990, Pharmacology & therapeutics.

[47]  N. S. Cook,et al.  The pharmacology of potassium channels and their therapeutic potential. , 1988, Trends in pharmacological sciences.

[48]  M. Lazdunski,et al.  The Apamin-Sensitive Ca 2+ -Dependent K + Channel: Molecular Properties, Differentiation, Involvement in Muscle Disease, and Endogeneous Ligands in Mammalian Brain , 1988 .

[49]  J. A. Mills,et al.  Benzylamine analogues of chemotherapeutic diamidines. , 1947, Journal of the Chemical Society.