Synthesis and structure-activity relationships of fused imidazopyridines: A new series of benzodiazepine receptor ligands

Journal of Medicinal Chemistry

Volumn 39, Issue 14, 1996, Pages 2844-2851

  Takada, Susumu ^a   Sasatani, Takashi ^a   Chomei, Nobuo ^a   Adachi, Makoto ^a   Fujishita, Toshio ^a   Eigyo, Masami ^a   Murata, Shunji ^a   Kawasaki, Kazuo ^a   Matsushita, Akira ^a  

^a SHIONOGI AND CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

2 (3 ISOXAZOLYL) 3,6,7,9 TETRAHYDROIMIDAZO[4,5 D]PYRANO[4,3 B]PYRIDINE MONOPHOSPHATE; 2 (4 CHLOROPHENYL) 5H PYRAZOLO[4,3 C]QUINOLIN 3 ONE; 2 PHENYL 5H PYRAZOLO[4,3 C]QUINOLIN 3 ONE; 3,6,7,9 TETRAHYDRO 2 (3 ISOXAZOLYL)IMIDAZO[4,5 D]PYRANO[4,3 B]PYRIDINE; BENZODIAZEPINE RECEPTOR; BENZODIAZEPINE RECEPTOR BLOCKING AGENT; DIAZEPAM; FLUMAZENIL; IMIDAZOPYRIDINE DERIVATIVE; IMIDAZOQUINOLINE DERIVATIVE; PENTETRAZOLE; UNCLASSIFIED DRUG;

ANIMAL MODEL; ANTICONVULSANT ACTIVITY; ARTICLE; COGNITION; CONVULSION; DRUG OVERDOSE; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; INTRAVENOUS DRUG ADMINISTRATION; MALE; MOUSE; NEUROPHARMACOLOGY; NONHUMAN; ORAL DRUG ADMINISTRATION; SEDATION; SENILE DEMENTIA; STRUCTURE ACTIVITY RELATION; TRANQUILIZING ACTIVITY;

ANIMALS; ANTICONVULSANTS; DIAZEPAM; IMIDAZOLES; LIGANDS; MALE; MICE; PYRIDINES; QUINOLINES; RATS; RATS, WISTAR; RECEPTORS, GABA-A; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0029944298     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9600609     Document Type: Article

References (19)

1. Haefely, W.; Kyburz, E.; Gerecke, M.; Mohler, H. Recent Advances in the Molecular Pharmacology of Benzodiazepine Receptors and in the Structure-activity Relationships of Their Agonists and Antagonists. In Advances in Drug Research; Testa, B., Ed.; Academic Press: New York, 1985; Vol. 14, pp 165-322.
2. Braestrup, C.; Honore, T.; Nielsen, M.; Petersen, E. N.; Jensen, H. Ligands for benzodiazepine receptors with positive and negative efficacy. Biochem. Pharmacol. 1984, 33, 859-862.
3. A receptor subunit for benzodiazepine pharmacology. Nature 1989, 338, 582-585.
4. Brogden, R. N.; Goa, K. L. Flumazenil. A reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991, 42, 1061-1089.
5. Venault, P.; Chapouthier, G.; de Cabalho, L. P.; Simiand, J.; Moore, M.; Dodd, R. H.; Rossier, J. Benzodiazepine impairs and β-carboline enhances performance in learning and memory tasks. Nature 1986, 321, 864-866.
6. Matsushita, S.; Kawasaki, K.; Matsubara, K.; Eigyo, M.; Shindo, H.; Takada, S. Activation of brain function by S-135, a benzodiazepine receptor inverse agonist. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1988, 12, 951-966.
7. Sarter, M.; Schneider, H. H.; Stephens, D. N. Treatment strategies for senile dementia: antagonist β-carbolines. Trends Neurosci. 1988, 11, 13-17.
8. Shindo, H.; Takada, S.; Murata, S.; Eigyo, M.; Matsushita, A. Thienylpyrazoloquinolines with high affinity to benzodiazepine receptors: continuous shift from inverse agonist to agonist properties depending on the size of the alkyl substituent. J. Med. Chem. 1989, 32, 1213-1217.
9. Bachman, G. B.; Welton, D. E.; Jenkins, G. L.; Christian, J. E. Quinoline derivatives from 3-nitro-4-hydroxyquinoline. J. Am. Chem. Soc. 1947, 69, 365-371.
10. Tohda, Y.; Eiraku, M.; Nakagawa, T.; Usami, Y.; Ariga, M.; Kawashima, T.; Tani, K.; Watanabe, H.; Mori, Y. Nucleophilic reaction upon electron-deficient pyridone derivatives. X. Onepot synthesis of 3-nitropyridines by ring transformation of 1-methyl-3,5-dinitro-2-pyridone with ketones or aldehydes in the presence of ammonia. Bull. Chem. Soc. Jpn. 1990, 63, 2820-2827.
11. Takada, S.; Shindo, H.; Sasatani, T.; Chomei, N.; Matsushita, A.; Eigyo, M.; Kawasaki, K.; Murata, S.; Takahara, Y.; Shintaku, H. Thienylpyrazoloquinolines: potent agonists and inverse agonists to benzodiazepine receptors. J. Med. Chem. 1988, 31, 1738-1745.
12. Hunkeler, W.; Mohler, H.; Pieri, L.; Polc, P.; Bonetti, E. P.; Cumin, R.; Schaffner, R.; Haefely, W. Selective antagonists of benzodiazepines. Nature 1981, 290, 514-516.
13. Yokoyama, N.; Ritter, B.; Neubert, A. D. 2-Arylpyrazolo-[4,3-c]quinolin-3-ones: novel agonist, partial agonist, and antagonist of benzodiazepines. J. Med. Chem. 1982, 25, 337-339.
14. Allen, M. S.; Skolnick, P.; Cook, J. M. Synthesis of novel phenyl-2H-pyrazolo[4,3-c]isoquinolin-3(3H)-ones at benzodiazepine receptors. J. Med. Chem. 1992, 35, 368.
15. Because the N3H imidazoquinolines are more stable than the N5H tautomers, the reviewer proposed an alternative alignment of the pyrazoloquinolines with the N3H tautomers of the imidazoquinolines as shown in the following figure (see below). As the reviewer suggested, this alignment is consistent with Fryer's observation that substituents on ring A of pyrazoloquinolines can mimic the pharmacological effects of substituents on ring D. Fryer had proposed that pyrazoloquinolines possessing substituents on ring A bind in an inverted orientation to BZR so that substituents on ring A occupy volumes comparable to ring D substituents. (For Fryer's work, see: Fryer, R. I.; Zhang, P.; Rios, R.; Gu, Z. Q.; Basile, A. S.; Skolnick, P. Structure-activity relationship studies at benzodiazepine receptors (BzR): a comparison of the substituent effects of pyrazoloquinolinone analogues. J. Med. Chem. 1993, 36, 1669-1673.) Nonetheless, the inverted orientation to the BZR seems to be at variance with the effects of the alkyl group on the isoxazole rings which led to the shifts from inverse agonist to agonist (e.g., 4a vs 4b, 14c vs 15c, 14d vs 15d) in analogy with data reported for the 2-thienylpyrazoloquinolines. Thus, compounds 4b and 15c,d do not possess any substituent at the 7- or 8-position which is needed to exhibit effects toward agonist in the inverted model. Although some of our data (e.g., effects of the 7-halo substituents of 4f,g) may be attributed to this model, the entire structure-activity relationships can be well accounted for by the alignment using the N5H imidazoquinolines shown in Figures 1 and 2. Equation Prasented
16. While the muscle relaxation effects of Bb and 15b are 40- and 10-fold less potent than that of diazepam, respectively (traction test using mice), both possessed potent anxiolytic effects comparable to diazepam (anticonflict test using rats). The detailed data will be reported elsewhere.
17. Surrey, A. R.; Cutler, R. The synthesis of some 3-nitro- and 3-amino-4-dialkylaminoalkylaminoquinoline derivatives. A. J. Am. Chem. Soc. 1961, 73, 2413-2416.
18. Sybyl version 6.10; Tripos Inc., St. Louis, MO 63144.
19. QCPE Program #455 (Quantum Chemistry Program Exchange, Department of Chemistry, Indiana University, Bloomington, IN 47405); J. J. P. Stewart, Frank J. Seiler Research Laboratory, U.S. Air Force Academy, CO 80840.