Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity

Current Topics in Medicinal Chemistry

Volumn 6, Issue 7, 2006, Pages 723-732

  Sax, Michael ^a   Wünsch, Bernhard ^a  

^a UNIVERSITY OF MÜNSTER   (Germany)

Author keywords

Analgesic; Anesthetic; Levoxadrol; Piperidine ring; Propiophenone derivative; Spirocyclic dioxolanes

Indexed keywords

1,3 DIOXOLANE DERIVATIVE; ACETYLSALICYLIC ACID; ANALGESIC AGENT; BUDIPINE; CARBON; CODEINE; DEXOXADROL; ETOXADROL; KETAMINE; LOCAL ANESTHETIC AGENT; MEMANTINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NARCOTIC ANALGESIC AGENT; OXYGEN; PAPAVERINE; PHENCYCLIDINE; PIPERIDINE DERIVATIVE; PLACEBO; PROCAINE;

ANTICONVULSANT ACTIVITY; CLINICAL TRIAL; DISEASE MODEL; DISEASE SEVERITY; DOSE RESPONSE; DRUG BINDING SITE; DRUG EFFICACY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; IN VITRO STUDY; MOLECULAR MODEL; NONHUMAN; PAIN; PHARMACOPHORE; PROTEIN INTERACTION; RECEPTOR AFFINITY; RESPIRATION DEPRESSION; REVIEW; SEIZURE; SPASMOLYSIS; STEREOCHEMISTRY; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; UNPLEASANT DREAM;

ANIMALS; DIOXOLANES; EXCITATORY AMINO ACID ANTAGONISTS; HUMANS; MODELS, MOLECULAR; OXYGEN; PIPERIDINES; RECEPTORS, N-METHYL-D-ASPARTATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33646552687     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802606776894483     Document Type: Review

References (37)

1. a Hardie, W. R.; Hidalgo, J.; Halverstadt, I. F.; Allen, R. E. 4-(2-piperidyl)-1,3-dioxolanes with Local Anesthetic, Spasmolytic, and Central Nervous System Activity. J. Med. Chem. 1966, 9, 127-136.
2. b Hardie, W. R.; Aaron, J. E. Dioxolane substituted Compounds. Patent 1199110, 1970.
3. Thurkauf, A.; Zenk, P. C.; Balster, R. L.; May, E. L.; George, C.; Carroll, F. I.; Mascarella, S. W.; Rice, K. C.; Jacobson, A. E.; Mattson, M. V. Synthesis, Absolute Configuration, and Molecular Modeling Study of Etoxadrol, a Potent Phencyclidine-like Agonist. J. Med. Chem. 1988, 31, 2257-2263.
4. Jacobson, A. E.; Harrison Jr., E. A.; Mattson, M. V.; Rafferty, M. F.; Rice, K. C.; Woods, J. H.; Winger, G.; Solomon, R. E.; Lessor, R. A.; Silverton, J. V. Enantiomeric and Diastereomeric Dioxadrols: Behavioral, Biochemical and Chemical Determination of the Configuration Necessary for Phencyclidine-Like Properties. J. Pharmacol. Exp. Ther. 1987, 243, 110-117.
5. Brown, L. W.; Forist, A. A. Kinetics of Acid-Catalyzed Hydrolysis of Dexoxadrol. J. Pharm. Sci. 1973, 62, 1365-1367.
6. Hidalgo, J.; Thompson, C. R. Pharmacology of the Dextrorotatory Isomer, CL-911-C, and of the Levorotatory Isomer, CL-912-C, of the Lower Melting Racemate of 2,2-Diphenyl-4-(2-Piperidyl)-1,3-Dioxolance HCI. Arch. Int. Pharmacodyn. 1965, 153, 105-125.
7. Lasagna, L.; Pearson, J. W. Analgesic and psychotomimetic properties of Dexoxadrol. Proc. Soc. Exp. Biol. Med. 1965, 118, 352-354.
8. Williams, M. W.; Williford, Jr., E. A.; Williams, C. S.; Towne, J. C. Clinical Analgesic Activity of Dexoxadrol. Arch. Int. Pharmacodyn. 1969, 178, 26-30.
9. Kast, E. C. A contribution to the understanding of the pain process through observation of the analgesic properties of Dexoxadrol. Int. J. Neuropsychiatry 1967, 3, 15-19.
10. Allen, R. E.; Thompson, C. R.; Hildolgo, J. Ger. Patent 2001616, 1970;
11. Chem. Abstr. 1971, 74, 131296.
12. Lasagna, L.; Pearson, J. W. Analgesic and psychotomimetic properties of dexoxadrol. Proc. Soc. Exp. Biol. Med. 1965, 118, 352-354.
13. Tang, A. H.; Kirch, J. D. Analgetic activities of etoxadrol in the rhesus monkey and in mice. Anesth. Analg. 1973, 52, 577-583.
14. Priano, L. L.; Turbow, M. E.; Wilson, R. D.; Traber, D. L. Effect of etoxadrol on coronary bloodflow and cardiac dynamics. Proc. Soc. Exp. Biol. Med. 1974, 145, 37-41.
15. Hidalgo, J.; Dileo, R. M.; Rikimaru, M. T.; Guzman, R. J.; Thompson, Chr. R. Anesth. Analg. 1971, 50, 231-239.
16. Wilson, R. D.; Allen, Ch. R.; Creson, D.; Schmitt, R.; Barratt, E.; Traber, D. L.Operant behavior and neurophysiological observations of normal human volunteers receiving CL 1848C [Etoxadrol], a new dissociative anesthetic. Tex. Rep. Biol. Med. 1973, 31, 239-248.
17. Frederickson, E. L.; Longnecker, D. E.; Allen, G. W. Clinical investigation of a new intravenous anesthetic-etoxadrol hydrochloride (CI-1848; U-37862A). Anesth. Analg. 1976, 55, 335-339.
18. Mendelson, L. G.; Kerchner, G. A.; Katra, V.; Zimmermann, D. H.; Leander, J. D. Phencyclidine receptors in rat brain cortex. Biochem. Pharmacol. 1984, 33, 3529-3535.
19. 3H-Phencyclidine in Brain Membranes. Life Sci. 1982, 30, 2147-2154.
20. Wong, E. H. F.; Kemp, J. A. Sites for Antagonism on the N-Methyl-D-Aspartate Receptor Channel Complex. Annu. Rev. Pharmacol. Toxicol. 1991, 31, 401-425.
21. Ornstein, P. L.; Zimmerman, D. M.; Leander, J. D.; Mendelsohn, L.; Reel, J. K.; Evrard D. A. The Search for a Phencyclidine (PCP) Antagonist: PCP-like Effects of a Series of Substituted Dioxolanes Related to Dexoxadrol. In Sigma and Phencyclidine-like Compounds as Molecular Probes in Biology; Domino, E. F; Kamenka, J.-M.; Eds.; NPP Books: Ann Arbor, 1988, 19-55.
22. Thurkauf, A.; Mattson, M. V.; Richardson, S.; Mirsadeghi, S.; Ornstein, P. L.; Harrison, Jr., E. A.; Rice, K. C.; Jacobson, A. E.; Morin, J.A. Analogues of the Dioxolanes Dexoxadrol and Etoxadrol as Potential Phencyclidine-like Agents. Synthesis and Structure-Activity Relationships. J. Med. Chem. 1992, 35, 1323-1329.
23. Harrison, Jr., E. A.; Rafferty, M. F.; Rice, K. C.; Creveling, C. R.; Winger, G. D.; Woods, J. H.; Jacobson, A. E. Evidence for separation of anesthetic activity from prototypic phencyclidine action in drug discrimination by molecular modification of dioxadrol, a phencyclidine-like dissociative anesthetic. NIDA Res. Monograph 1985, 55, 90-96.
24. Thurkauf, A.; Mattson, M. V.; Huguenin, Ph. N.; Rice, K. C.; Jacobson, A. E. Etoxadrol-meta-isothiocyanate: a potent" enantioselective, electrophilic affinity ligand for the phencyclidine-binding site. FEBS Lett. 1988, 238, 369-374
25. Sax, M. Dissertation 2006, unpublished results.
26. Hardie, W. R.; Creek, W. Carbocyclic Substituted Piperidyl Dioxanes. US Patent 1966, 3, 256,28.
27. Sax, M.; Wünsch, B. Bioorg. Med. Chem. (submitted).
28. Aepkers, M.; Wünsch, B. Synthesis and NMDA-Receptor Affinity of Ring and side Chain Homologous Dexoxadrol Derivatives. Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67-75.
29. Aepkers, M.; Wünsch, B. Structure Affinity Relationship Studies of Novel NMDA Receptor Antagonists Derived from Dexoxadrol and Etoxadrol. Bioorg. Med. Chem. 2005, 13, 6836-6849.
30. Utech, T. Synthese und Struktur-Affinitätsbezeichnungen neuer NMDA-Rezeptor-Antagonisten mit 1,3-Dioxan-Struktur. Dissertation 2003, (unpublished results).
31. Brasili, L.; Sorbi, C.; Franchini, S.; Manicardi, M.; Angeli, P.; Marucci, G.; Leonardi, A.; Poggesi, E. 1,3-Dioxolane-Based Ligands as a Novel Class of α1-Adrenoceptor Antagonists. J. Med. Chem. 2003, 46, 1504-1511. 1892-1897.
32. Dei, S.; Bellucci, C.; Buccioni, M.; Ferraroni, M.; Gualtieri, F.; Guandalini, L.; Manetti, D.; Matucci, R.; Romanelli, M. N.; Scapecchi, S.; Teodori, E. Synthesis and Cholinergic Affinity of Diastereomeric and Enantiomeric Isomers of 1-Methyl-2-(2-methyl-1,3-dioxolan-4-yl)-pyrrolidine, 1-Medlyl-2-(2-methyl-1,3-oxathiolan-5-y1)pyrrolidine and of their Iodomethylates. Bioorg. Med. Chem. 2003, 11, 3153-3164.
33. Shapiro, G.; Floersheim. P.; Amstutz, R.; Boddeke, H.; Bolliger, G.; Cottens, S.; Enz, A.; Gmelin, G.; Gull, P.; Supavilai, P. Muscarinic Agonist SAR of Azaspirodioxolanes. Bioorg. Med. Chem. Lett. 1992, 2, 815-820.
34. Piergentili, A.; Gentili, F.; Ghelfi, F.; Marucci, G.; Pigini, M.; Quaglia, W.; Giannella, M. Muscarinic Subtypes Profile Modulation within a Series of New Antagonists, Bridged Bicyclic Derivatives of 2,2-Diphenyl-[1,3]-dioxolan4-ylmethyl-dimethylamine. Bioorg. Med. Chem. 2003, 11, 3901-3911.
35. Brady, K. T.; Woolverton, W. L.; Balster, R. L. Phencyclidine (PCP) and phencyclidine-like compounds: a molecular graphics-molecular mechanics study. J. Pharmacol. Exp. Ther. 1982, 220, 56-62.
36. Laguerre, M.; Elhaoui, M.; Carpy, A. Modeling of noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. In Trends QSAR Mol. Modell. 92, Proc. Eur. Symp. Struct.-Act. Relat.: QSAR Mol. Modell; Wermuth, C.-G.; Ed.; Escom Publisher: Leiden, 1993, 444-445.
37. Elhallaoui, M.; Laguerre, M.; Carpy, A. J. Molecular modeling of noncompetitive antagonists of the NMDA receptor: proposal of a pharmacophore and a description of the interaction mode. Mol. Model 2002, 8, 65-72.