Structure-activity relationships and effects on neuroactive steroid synthesis in a series of 2-phenylimidazo[1,2-a]pyridineacetamide peripheral benzodiazepine receptors ligands

Journal of Medicinal Chemistry

Volumn 48, Issue 1, 2005, Pages 292-305

  Trapani, Giuseppe ^a   Laquintana, Valentino ^a   Denora, Nunzio ^a   Trapani, Adriana ^a   Lopedota, Angela ^a   Latrofa, Andrea ^a   Franco, Massimo ^a   Serra, Mariangela ^b,c   Pisu, Maria Giuseppina ^b,c   Floris, Ivan ^b   Sanna, Enrico ^b   Biggio, Giovanni ^b,c   Liso, Gaetano ^a  

^a UNIVERSITY OF BARI   (Italy)

^b Sezione di Neuroscienze   (Italy)

^c CNR   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

2 (4 CHLOROPHENYL) 3 (2 OXO 2 PIPERIDIN 1 YLETHYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDINE; 2 (4 CHLOROPHENYL) 3 [(6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL) ACETYL] 1,2,3,4 TETRAHYDROISOQUINOLINE; 2 (4 CHLOROPHENYL) 6,8 DICHLORO 3 (2 OXO 2 PYRROLIDIN 1 YLETHYL)IMIDAZO[1,2 A]PYRIDINE; 2 (6,8 DICHLORO 2 PHENYLIMIDAZO[1,2 A]PYRIDIN 3 YL) N PYRIDIN 4 YLACETAMIDE; 2 PHENYL 3 (2 OXO 2 PIPERIDIN 1 YLETHYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDINE; 2 PHENYL 3 [(6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL) ACETYL] 1,2,3,4 TETRAHYDROISOQUINOLINE; 2 PHENYL 6,8 DICHLORO 3 (2 OXO 2 PYRROLIDIN 1 YLETHYL)IMIDAZO[1,2 A]PYRIDINE; ACETAMIDE DERIVATIVE; BENZODIAZEPINE RECEPTOR; IMIDAZOPYRIDINE DERIVATIVE; N BENZYL N N BUTYL (2 PHENYL 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL)ACETAMIDE; N BENZYL N TERT BUTYL[2 (4CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL)ACETAMIDE; N CYCLOHEXYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N CYCLOHEXYL [2 PHENYL 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N METHYL N PHENYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N N BUTYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N N BUTYL N 4 NITROBENZYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N N BUTYL N PHENYL [2 (4 CHLOROPHENYL) 6 CHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N N BUTYL N PHENYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N PHENYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N,N BUTYL N PHENYL (2 PHENYL 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL)ACETAMIDE; N,N BUTYL,N METHYL (2 PHENYL 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL)ACETAMIDE; N,N BUTYL,N METHYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZOL[1,2 A]PYRIDIN 3 YL)]ACETAMIDE; N,N DI N BUTYL [2 (4 CHLOROPHENYL) 6 CHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N,N DI N BUTYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N,N DI N BUTYL [2 (4 CHLOROPHENYL) 8 CHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N,N DI N HEXYL [2 (4 CHLOROPHENYL) 6 CHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; N,N DI N HEXYL [2 (4 CHLOROPHENYL) 6,8 DICHLOROIMIDAZO[1,2 A]PYRIDIN 3 YL]ACETAMIDE; STEROID; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; AROMATIZATION; ARTICLE; BRAIN CORTEX; CONTROLLED STUDY; DRUG CONFORMATION; DRUG DESIGN; DRUG EFFECT; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; IN VITRO STUDY; IN VIVO STUDY; MALE; NONHUMAN; RAT; STEROIDOGENESIS; STRUCTURE ACTIVITY RELATION;

ACETAMIDES; AMIDES; ANIMALS; BIOCHEMISTRY; BLOOD; BRAIN; CENTRAL NERVOUS SYSTEM AGENTS; DRUG EVALUATION, PRECLINICAL; ELECTROPHYSIOLOGY; FEMALE; LIGANDS; MALE; NITROGEN; OOCYTES; PERIPHERAL NERVOUS SYSTEM AGENTS; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, GABA-A; STEROIDS; STRUCTURE-ACTIVITY RELATIONSHIP; XENOPUS;

EID: 19944429835     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049610q     Document Type: Article

References (40)

1. Galiegue, S.; Tinel, N.; Casellas, P. The Peripheral Benzodiazepine Receptors: a Promising Therapeutic Drug Target. Curr. Med. Chem. 2003, 10, 1563-1572.
2. Papadopulos, V.; Guarneri, P.; Krueger, K. E.; Guidotti, A.; Costa, E. Pregnenolone Biosynthesis in C6 Glioma Cell Mitochondria: Regulation by a Mitochondrial Diazepam Binding Inhibitor Receptor. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5113-5117.
3. Guarneri, P.; Papadopulos, V.; Krueger, K. E.; Guidotti, A.; Costa, E. Regulation of Pregnenolone Synthesis in C6-2B Glioma Cells by 4′-Chlordiazepam. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5118-5122.
4. Majewska, M. D.; Harrison, N. L.; Schwartz, R. D.; Barker, J. L.; Paul, S. M. Steroid Hormone Metabolites are Barbiturate-like Modulators of the GABA Receptor. Science 1986, 232, 1004-1007.
5. A Receptor. Trends Pharmacol. Sci. 1987, 8, 224-227.
6. A Receptor-Mediated Currents via a Reduction of Channel Opening Frequency. Brain Res. 1989, 489, 190-194.
7. A Receptors. Neuron 1980, 4, 759-765.
8. Wu, F.; Gibbs, T. T.; Farb, D. H. Pregnenolone Sulfate: a Positive Allosteric Modulator at the N-Methyl-D-Aspartate Receptor. Mol. Pharmacol. 1991, 40, 333-336.
9. 11C]Methylated Quinoline-2-Carboxamides as Potential Radioligands for Visualization of Peripheral Benzodiazepine Receptors. J. Med. Chem. 2001, 44, 579-585.
10. Pike, V. W.; Halldin, C.; Crouzel, C.; Barrè, L.; Nutt, D. J.; Osman, S.; Shah, F.; Turton, D. R.; Waters, S. L.; Radioligands for PET Studies of Central Benzodiazepine Receptors and PK (Peripheral Benzodiazepine) Binding Sites - Current Status. Nucl. Med. Biol. 1993, 20, 503-525.
11. Guo, P.; Ma, J.; Li, S.; Guo, Z.; Adams, A. L.; Gallo, J. M. Targeted Delivery of a Peripheral Benzodiazepine Receptor Ligand-Gemcitabine Conjugate to Brain Tumors in a Xenograft Model. Cancer Chemother. Pharmacol. 2001, 48, 169-176.
12. Kupczyk-Subotkowaka, L.; Siahaan, T. J.; Basile, A.; Friedman, H. S.; Higgins, P. E.; Song, D.; Gallo, J. M. Modulation of Melphalan Resistance in Glioma Cells with a Peripheral Benzodiazepine Receptor Ligand-Melphalan Conjugate. J. Med. Chem. 1997, 40, 1726-1730.
13. Trapani, G.; Laquintana, V.; Latrofa, A.; Ma, J.; Reed, K.; Serra, M.; Biggio, G.; Liso, G.; Gallo, J. M. Peripheral Benzodiazepine Receptor Ligand-Melphalan Conjugates for Potential Selective Drug Delivery to Brain Tumors. Bioconjugate Chem. 2003, 14, 830-839
14. Maaser, K.; Grabowski, P.; Surter, A. P.; Hopfner, M.; Foss, H. D.; Stein, H.; Berger, G.; Gavish, M.; Zeitz, M.; Scherübl, A. P. Overexpression of the Peripheral Benzodiazepine Receptor is a Relevant Prognostic Factor in Stage III Colorectal Cancer. Clin. Cancer Res. 2002, 8, 3205-3209.
15. Hardwick, M.; Fertikh, D.; Culty, M.; Li, H.; Vidic, B.; Papadopoulos, V. Peripheral-type Benzodiazepine Receptor (PBR) in Human Breast Cancer: Correlation of Breast Cancer Cell Aggressive Phenotype with PBR Espression, Nuclear Localization, and PBR-Mediated Cell Proliferation and Nuclear Transport of Cholesterol. Cancer Res. 1999, 59, 831-842.
16. Katz, Y.; Eitan, A.; Gavish, M. Increased Density of Peripheral Benzodiazepine-Binding Sites in Ovarian Carcinomas as Compared with Benign Ovarian Tumors and Normal Ovaries. Clin. Sci. 1990, 78, 155-158.
17. Venturini, I.; Zaneroli, M. L.; Corsi, L.; Avallona, R.; Farina, F.; Alho, H.; Baraldi, C.; Ferrarese, C.; Pecora, N.; Frigo, M.; Ardizzone, G.; Arrigo, A.; Pellicci, R.; Baraldi, M. Up-Regulation of Peripheral Benzodiazepine Receptor System in Hepatocellular Carcinoma. Life Sci. 1998, 65, 1269-1280.
18. Veenman, L.; Gavish, M. Peripheral-type Benzodiazepine Receptors: Their Implication in Brain Disease. Drug Dev. Res. 2000, 50, 355-370.
19. Sutter, A. P.; Maaser, K.; Barthel, B.; Scherübl, H. Ligands of the Peripheral Benzodiazepine Receptor Induce Apoptosis and Cell Cycle Arrest in Oesophageal Cancer Cells: Involvement of the P38mapk Signaling Pathway. Br. J. Cancer 2003, 89, 564-572.
20. Sprengel, R.; Werner, P.; Seeburg, P. H.; Mukhin, A. G.; Santi, M. R.; Grayson, D. R.; Guidotti, A.; Krueger, K. E. Molecular Cloning and Expression of cDna Encoding a Peripheral-type Benzodiazepine Receptor. J. Biol. Chem. 1989, 264, 20415-20421.
21. 3H]Ro 5-4864. Mol. Pharmacol. 1982, 22, 26-32.
22. Le Fur, G.; Perrier, M. L.; Vaucher, N.; Imbault, F.; Flamier, A.; Uzan, A.; Renault, C.; Dubroeucq, M. C.; Gueremy, C. Peripheral Benzodiazepine Binding Sites: Effect of PK 11195, 1-(2-Chlorophenyl)-N-(1-Methylpropyl)-3- Isoquinolinecarboxamide I. In Vitro Studies. Life Sci. 1983, 32, 1839-1847.
23. Romeo, E.; Auta, J.; Kozikowski, A. P.; Ma, A.; Papadopoulos, V.; Puia, G.; Costa, E.; Guidotti, A. 2-Aryl-3-Indoleacetamides (FGIN-1): a New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor. J. Pharmacol. Exp. Ther. 1992, 262, 971-978.
24. Okujama, S.; Chaki, S.; Yoshikawa, R.; Ogawa, S.; Suzuki, Y.; Okubo, T.; Nakazato, A.; Nagamine, M.; Tomisawa, K. Neuropharmacological Profile of Peripheral Benzodiazepine Receptor Agonists, DAA1097 and DAA1106. Life Sci. 1999, 16, 1455-1464.
25. Campiani, G.; Nacci, V.; Fiorini, I.; De Filippis, M. P.; Garofalo, A.; Ciani, S. M.; Greco, G.; Novellino, E.; Williams, D. C.; Zisterer, D. M.; Woods, M. J.; Mihai, C.; Manzoni, C.; Mennini, T. Synthesis, Biological Activity, and SARs of Pyrrolobenzoxazepine Derivatives, a New Class of Specific "Peripheral-type" Benzodiazepine Receptor Ligands. J. Med. Chem. 1996, 39, 3445-3450.
26. Trapani, G.;Franco, M.; Ricciardi, L.; Latrofa, A.; Genchi, G.; Sanna, E.; Tuveri, F.; Cagetti, E.; Biggio, G.; Liso, G. Synthesis and Binding Affinity of 2-Phenylimidazo[1,2-a]pyridine Derivatives for Both Central and Peripheral Benzodiazepine Receptors. A New Series of High-Affinity and Selective Ligands for the Peripheral Type. J. Med. Chem. 1997, 40, 3109-3118.
27. Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.; Sanna, E.; Biggio, G.; Liso, G. Novel 2-Phenylimidazo-[1,2-a]pyridine Derivatives as Potent and Selective Ligands for Peripheral Benzodiazepine Receptors. Synthesis, Binding Affinity, and In Vivo Studies. J. Med. Chem. 1999, 42, 3934-3941.
28. 3H]Labelled Potent and Selective Peripheral Benzodiazepine Receptor Ligand CB 34. J. Labelled Compd. Radiopharm. 2001, 44, 521-528.
29. Serra, M.; Madau, P.; Chessa, M. F.; Caddeo, M.; Sanna, E.; Trapani, G.; Franco, M.; Liso, G.; Purdy, R. H.; Barbaccia, M. L.; Biggio, G. 2-Phenyl-imidazo[1, 2-a]pyridine Derivatives as Ligands for Peripheral Benzodiazepine Receptors: Stimulation of Neurosteroid Synthesis and Anticonflict Action in Rats. Br. J. Pharmacol. 1999, 127, 177-187.
30. Anzini, M.; Cappelli, A.; Vomero, S.; Seeber, M.; Menziani, M.; Langer, T.; Hagen, B.; Manzoni, C.; Bourguignon, J.-J. Mapping and Fitting the Peripheral Benzodiazepine Receptor Binding Site By Carboxamide Derivatives. Comparison of Different Approaches to Quantitative Ligand-Receptor Interaction Modeling. J. Med. Chem. 2001, 44, 1134-1150.
31. Cinone, N.; Holtje, H.-D.; Carotti, A. Development of a Unique 3D Interaction Model of Endogenous and Synthetic Peripheral Benzodiazepine Receptor Ligands. J Comput.-Aided Mol. Des 2000, 14, 753-768.
32. Roy, K.; De, A. U.; Sengupta, C. QSAR of Peripheral Benzodiazepine Receptor Ligand 2-Phenylimidazo[1,2-a]pyridine Derivatives with Physicochemical Parameters. Indian J. Biochem. Biophys. 2003, 40, 203-208.
33. Hart, P. A.; Rich, D. H. Stereochemical Aspects of Drug Action I: Conformational Restriction, Steric Hindrance, and Hydrophobic Collapse. In The Practice of the Medicinal Chemistry; Wermuth, C. G., Ed.; Academic Press Limited: New York, 1996; pp 393-412.
34. CLOG P for Windows Vers. 4.0 (BioByte Corp., Claremont, CA).
35. ACD/Labs package, release 5.0 (Advanced Chemistry Development Inc., Toronto, Ontario, Canada).
36. Verloop, A. The STERIMOL Approach to Drug Design;. Dekker: New York, 1987.
37. 3H]CB34, a Selective Ligand for Peripheral Benzodiazepine Receptors, to Rat Brain Membranes. Eur. J. Pharmacol. 2001, 432, 129-134.
38. Mao, C. C.; Guidotti, A.; Costa, E. Interaction Between γ-Aminobutyric Acid and Guanosine Cyclic 3′,5′-Monophosphate in Rat Cerebellum. Mol. Pharmacol. 1974, 10, 736-745.
39. A Receptor Function After Acute Stress. Neuroendocrinology 1996, 63, 166-172.
40. Purdy, R. H.; Morrow, A. L.; Blinn, J. R.; Paul, S. M. Synthesis, Metabolism and Pharmacological Activity of 3-α-Hydroxy-Steroids Which Potentiate GABA-Receptor-Mediated Chloride Ion Uptake In Rat Cerebral Cortical Synaptoneurosomes. J. Med. Chem. 1990, 33, 1572-1581.