3060 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Maillard et al.
(10) (a) Dong, L. P.; Wang, T. Y.; Zhu, J . Effects of Carbamazepine
on Hypoxic and Ischemic Brain Damage in Mice. Chung Kuo
Yao Li Hsueh Pao 1994, 15, 257-259. (b) Murakami, A.; Furui,
T. Neurosurg. 1994, 34, 1047-1051.
(28) (a) Oldham, W.; J ohns, I. B. Electron Sharing Ability of Organic
Radicals. X. Alpha-Substituted Tetrahydroquinolines. J . Am.
Chem. Soc. 1939, 61, 3289-3291. (b) Goldstein, S. W.; Dambek,
P. J . 2-Substituted 1,2,3,4-Tetrahydroquinolines from Quinoline.
Synthesis 1989, 3, 221-222.
(29) Honel, M.; Vierhapper, F. W. Selectivity in the Hydrogenation
of 6- and 8-Substituted-Quinolines. J . Chem. Soc., Perkin Trans.
I 1980, 1933-1939.
(30) Scherz, W. M.; Fialeix, M.; Fischer, J .; Reddy, N.; Server, A.;
Sonders, M.; Tester, B.; Weber, E.; Wong, S.; Keana, J . Synthesis
and Structure-Activity Relationships of N,N′-Di-o-tolylguani-
dine Analogues, High-Affinity Ligands for the Haloperidol-
Sensitive σ Receptor. J . Med. Chem. 1990, 33, 2421-2429.
(31) Bae, D. H.; Shine, H. J . Photobenzidine rearrangements. 6.
Mechanism of the Photodecomposition of 1,4-diaryl-1,4-dialkyl-
2-tetrazines. J . Org. Chem. 1980, 45, 4448-4455.
(32) Durant, G. J .; Magar, S. S. Prepn. of Substd. Guanidine(s) from
Cyanamide and Amine - Using a Lewis Acid Catalyst or by a
Non-Catalytic Process in which Steric Hindrance is Reduced by
Using a Mono-Substid. Cyanamide. U.S. Patent 5298657.
(33) (a) Scheuer, T.; Auld, V. J .; Boyd, S.; Offord, J .; Dunn, R.;
Catteral, W. A. Functional Properties of Rat Brain Sodium
Channels Expressed in a Somatic Cell Line. Science 1990, 247,
854-858. (b) West, J . W.; Scheuer, T.; Maechler, L.; Catteral,
W. A. Efficient Expression of Type IIA Na+ Channel R Subunit
in a Somatic Cell Line. Neuron 1992, 5, 59-70.
(11) Pauwels, P. J .; Leysen, J . E.; J anssen, P. A. J . Ca2+ and Na+
Channels Involved in Neuronal Cell Death. Protection by
Flunarizine. Life Sci. 1991, 48, 1881-1893.
(12) Ginsberg, M. D. Efficacy of Calcium Channel Blockers in Brain
Ischemia: a Critical Assessment. In Pharmacology of Cerebral
Ischemia; Krieglstein, J ., Ed.; Wissenschaftliche Verlags-
gesellschaft: Stuttgart, 1988; pp 65-73.
(13) Bowersox, S. S.; Singh, T.; Nadasdi, L.; Zukowska-Grojec, Z.;
Valentino, K.; Hoffman, B. B. Cardiovascular Effects of Omega-
conopeptides in Conscious Rats: Mechanisms of Action. J .
Cardiovasc. Pharmacol. 1997, 20, 756-764.
(14) (a) Uchitel, O. D.; Protti, D. A.; Sanchez, V.; Cherksey, B. D.;
Sugimori, M.; Llina`s, R. P-type Voltage-dependent Calcium
Channel Mediates Presynaptic Calcium Influx and Neurotrans-
mitter Release in Mammalian Synapses. Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 3330-3333. (b) Bowersox, S. S.; Miljanich, G.
P.; Sugiura, Y.; Li, C.; Nadasdi, L.; Hoffman, B. B.; Ramachan-
dran, J .; Ko, C.-P. Differential Blockade of Voltage-Sensitive
Calcium Channels at the Mouse Neuromuscular J unction By
Novel ω-Conopeptides and ω-Agatoxin-IVA. J . Pharmacol. Exp.
Ther. 1995, 273, 248-256.
(15) Nagy, P. I.; Durant, J . G. Monte Carlo Simulation of the
Counterion Effect on the Conformational Equilibrium of the
N,N′-Diphenylguanidinium ion. J . Phys. Chem. 1996, 104, 1452-
1463.
(16) Alagona, G.; Ghio, C.; Nagy, P. I.; Durant, G. J . Theoritical
Studies on the Relative Stability of Neutral and Protonated N,N′-
Diarylguanidines in Aqueous Solution Using Continuum Solvent
Models. J . Phys. Chem. 1994, 98, 5422-5430.
(17) The authors propose the term “lockamer” to refer to a rigid or
semirigid scaffold which mimics the conformation of one or a
set of rotamers of the flexible template from which it is derived.
The term “foldamer” has been recently introduced.18.
(18) Appela, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.;
Gellman, S. H. â-Peptide Foldamers: Robust Helix Formation
in a New Family of â-Amino Acid Oligomers. J . Am. Chem. Soc.
1996, 118, 13071-13072.
(19) (a) Mohamdi, F.; Richards, N. G. J .; Guiga, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W.
C. MacroModel - An Integrated Software System for Modeling
Organic and Bioorganic molecules Using Molecular Mechanics.
J . Comput. Chem. 1990, 11, 440-467. (b) Still, W. C.; Tempczyk,
A.; Hawley, R. C.; Hendrickson, T. Semianalytical Treatment
of Solvation for Molecular Mechanics and Dynamics. J . Am.
Chem. Soc. 1990, 112, 6127-6129. (c) Weiner, S. J .; Kollman,
P. A.; Case, D. A.; Chandra Singh, U.; Ghio, C.; Alagona, G.;
Profeta, S., J r.; Weiner, P. A New Force Field for Molecular
Mechanical Simulation of Nucleic Acids and Proteins. J . Am.
Chem. Soc. 1984, 106, 765.
(20) Reddy, N. L.; Amitay, O.; Berlove, D.; Fan, W.; Fischer, J . B.;
Magar, S. S.; Wolcott, T.; Yost, E.; Durant, G. J . N,N′-Diaryl-
guanidines: Synthesis and Antiseizure Activity in the Audio-
genic DBA/2 Mouse Model. 211th American Chemical Society
National Meeting, New Orleans, LA, 1996; MEDI 57.
(21) Hu, L. Y.; Durant, G.; Guo, J . Q.; Maillard, M.; Wolcott, T.;
Berlove, D. Synthesis and Structure-Activity Relationships of
Substituted N-aryl-N-aralkylguanidines as Antiseizure Agents.
214th American Chemical Society National Meeting, Las Vegas,
NV, 1997; MEDI 32.
(22) Ishikawa, F.; Watanabe, Y.; Saegusa, J . Cyclic Guanidines. IX.
Synthesis of 2-Amino-3,4-dihydroquinazolines as Blood Platelet
Aggregation Inhibitors. Chem. Pharm. Bull. 1980, 28, 1357-
1364.
(23) Wanzlick, H.; Lachmann, B.; Schikora, E. Zur Bildung und
Reaktivita¨t des Bis-[1.3-diphenyl-imidazolidinylidens-(2)]. Chem.
Ber. 1965, 98, 3170-3176.
(24) Hiltmann, R.; Wollweber, H.; Hermann, G. 2-Amino-1-(chlo-
rophenyl)-2-imidazolines as Birds Repellents. Chem. Abstr. 1973,
78, 136283n.
(34) Gordon, D.; Merrick, D.; Auld, V.; Dunn, R.; Goldin, A. L.;
Davidson, N.; Catteral, W. A. Tissue-specific Expression of the
RI and RII Sodium Channel Subtypes. Proc. Natl. Acad. Sci.
U.S.A. 1987, 84, 8682-8688.
(35) Ahmed, C. M. I.; Ware, D. H.; Lee, S. C.; Patten, C. D.; Ferrer-
Montiel, A. V.; Schinder, A. F.; McPherson, J . D.; Wagner-
McPherson, C. B.; Wasmuth, J . J .; Evans, G. A.; Montal, M.
Primary Structure, Chromosomal Localization, and Functional
Expression of a Voltage-gated Sodium Channel from Human
Brain. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 8220-8224.
(36) Raysdale, D. S.; Scheuer, T.; Catteral, W. A. Frequency and
Voltage-dependent Inhibition of Type IIA Na+ Channels, Ex-
pressed in a Mammalian Cell Line, by Local Anesthetic, Anti-
arrhythmic, and Anticonvulsant Drugs. Mol. Pharmacol. 1993,
40, 756-765.
(37) Reith, M. E. A. [14C]Guanidinium Ion Influx into Na+ Channels
Preparations from Mouse Cerebral Cortex. Eur. J . Pharmacol.-
Mol. Pharmacol. Sect. 1990, 188, 33-41.
(38) Nachshen, D. A.; Blaustein, M. P. Influx of Calcium, Strontium,
and Barium in Presynaptic Nerve Endings. J . Gen. Physiol.
1982, 79, 1065-1087.
(39) Fisher, J . B.; Goldin, S. M.; Hu, L.-Y.; Katraggada, S.; Knapp,
A. G.; Margolin, L. Use of Substd. Guanidine(s) for Modulating
Neuro-transmitter Release for Treating e.g. Nerve Cell Death,
Alzheimer’s and Huntington’s Disease, Anxiety, Dementia and
Arteriosclerosis. PCT/US92/01050.
(40) (a) Seyfried, T. N. Audiogenic Seizures in Mice. Fed. Proc. 1979,
38, 2399-2404. (b) De Sarro, G. B.; Nistico, G.; Meldrum, B. S.
Anticonvulsant Properties of Flunarizine on Reflex and General-
ized Models of Epilepsy. Neuropharmacology 1986, 25, 695-701.
(41) (a) Catteral, W. A. Structure and Modulation of Na+ and Ca2+
Channels. In Challenges and Perspectives in Neuroscience;
Ottoson, D., Ed.; Elsevier Science Publishers B.V.: Amsterdam,
New York, 1995; pp 51-75. (b) Kisch, G. E. Na+ Channels:
Structure, Function, and Classification. Drug Dev. Res. 1994,
33, 263-276. (c) Catteral, W. A. Structure and Function of
Voltage-Sensitive Ion Channels. Science 1988, 242, 50-60.
(42) (a) Meldrum, B. S. The role of Glutamate in Epilepsy and other
CNS Disorders. Neurology 1994, 44, S14-S23. (b) Anticonvul-
sant Properties of Flunarizine on Reflex and Generalized Models
of Epilepsy. Neuropharmacology 1986, 25, 695-701.
(43) (a) Reddy, N. L.; Hu, L.-Y.; Cotter, R. E.; Fisher, J . B.; Wong,
W. J .; McBurney, R. N.; Weber, E.; Holmes, D. L.; Wong, S. T.;
Prasad, R.; Keana, J . F. W. Synthesis and Structure-Activity
Studies of N,N′-Diarylguanidine Derivatives. N-(1-Naphthyl)-
N′-(3-ethylphenyl)-N′-methylguanidine: A new Selective Non-
competitive NMDA Receptor Antagonist. J . Med. Chem. 1994,
37, 260-267. (b) Hu, L.-Y.; Guo, J . Q.; Magar, S.; Fischer, J . B.;
Burke-Howie, K.; Durant, G. J . Synthesis and Pharmacological
Evaluation of N-(2,5-disubstituted-phenyl)-N′-(3-substituted-
phenyl)-N′-methylguanidines as N-Methyl-D-Aspartate Receptor
Ion-channel Blockers. J . Med. Chem. 1997, 40, 4281-4289.
(44) (a) Trickelbank, M.; Singh, L.; Oles, R. J .; Preston, C.; Iversen,
S. D. The Behavioral Effects of MK-801: a Comparison with
Antagonist Acting Non-Competitively and Competitively at the
NMDA Receptor. Eur. J . Pharm. 1989, 167, 127-135. (b)
Rowley, M.; Leeson, P. D.; Stevenson, G. I.; Moseley, A. M.;
Stansfield, I.; Sanderson, I.; Robinson, L.; Baker, R.; Kemp, J .
A.; Marshall, G. R.; Foster, A. C.; Grimwood, S.; Trickelbank,
M. D.; Saywell, K. L. 3-Acyl-4-hydroxyquinolin-2(1H)-ones.
Systemically Active Anticonvulsants Acting by Antagonism at
the Glycine Site of the N-Methyl-D-Aspartate Receptor Complex.
(25) Walter, G.; Daniel, H.; Bechtel, W. D.; Brandt, K. New Tetra-
cyclic Guanidine Derivatives with H1-Antihistaminic Properties.
Arzneim.-Forsch/ Drug Res. 1990, 40, 440-446.
(26) (a) Bonin, M.; Chiaroni, A.; Riche, C.; Beloeil, J .-C.; Grierson,
D. S.; Husson, H.-P. On the Structure of 2,6-Dicyanopip-
eridines: a Correction. J . Org. Chem. 1987, 52, 382-385. (b)
Takahashi, K.; Mikajiri, T.; Kurita, H.; Ogura, K.; Lida, H.
Stereoselective Synthesis of 1-Substituted 2,6-Dicyanopipe-
ridines and Transformation of 2,6-Dialkylproducts of 1-Phenyl-
2,6-dicyanopiperidine to δ-Diketones and Cyclohexenones. J .
Org. Chem. 1985, 50, 4372-4375.
(27) Biggs, B. S.; Bishop, W. S. Decamethylenediamine. Org. Synth.
3, 229-230.