Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 1. Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives

Journal of Medicinal Chemistry

Volumn 41, Issue 5, 1998, Pages 728-741

  Cappelli, Andrea ^a   Anzini, Maurizio ^a   Vomero, Salvatore ^a   Mennuni, Laura ^b   Makovec, Francesco ^b   Doucet, Edith ^c   Hamon, Michel ^c   Bruni, Giancarlo ^a   Romeo, Maria R ^a   Menziani, M Cristina ^d   De Benedetti, Pier G ^d   Langer, Thierry ^e  

^a UNIVERSITY OF SIENA   (Italy)

^b Rotta Research Laboratorium   (Italy)

^c PITIÉ SALPÊTRIÈRE HOSPITAL   (France)

^d UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^e UNIVERSITY OF INNSBRUCK   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

2 (4 METHYL 1 PIPERAZINYL) 5H INDENO[1,2 B]PYRIDINE; 6 (4 METHYL 1 PIPERAZINYL) 7,8,8,10 TETRAHYDRO 8,10 ETHANOPHENANTHRIDINE; 6 (4 METHYL 1 PIPERAZINYL) 7,8,9,10 TETRAHYDROPHENANTHRIDINE; 6 NITROQUIPAZINE; GRANISETRON; PARTIAL AGONIST; PHENANTHRIDINE DERIVATIVE; PIPERAZINE DERIVATIVE; PYRIDINE DERIVATIVE; QUIPAZINE; SEROTONIN; SEROTONIN 3 AGONIST; SEROTONIN 3 ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; DOSE RESPONSE; DRUG ACTIVITY; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; MALE; MOUSE; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RAT;

ANIMALS; BENZENE; BINDING SITES; GLIOMA; GUANIDINE; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NEUROBLASTOMA; PHENANTHRIDINES; PIPERAZINES; QUINOLINES; QUIPAZINE; RATS; RECEPTORS, SEROTONIN; RECEPTORS, SEROTONIN, 5-HT3; SEROTONIN AGONISTS; SEROTONIN ANTAGONISTS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 15444349163     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970645i     Document Type: Article

References (50)

1. Hartig, P. R. Molecular Pharmacology of Serotonin Receptors. Experientia 1994, 71P (Suppl.), 93-102.
2. 3 Receptors. Med. Res. Rev. 1990, 10, 441-475 and references therein.
3. 3 Receptor Antagonists. Structure Affinity Relationships of Novel 1,7-Annelated Indole Derivatives. 1. J. Med. Chem. 1993, 36, 3693-3699 and references therein.
4. 3 Receptors. Pharmacol. Ther. 1990, 47, 181-202.
5. 3 Receptor Releases Dopamine from Rat Striatal Slices. Eur. J. Pharmacol. 1988, 155, 349-350.
6. 3 Receptors in Rat Cerebral Cortex and Nucleus Accumbens. Br. J. Pharmacol. 1991, 203, 1790-1794.
7. 3 Receptors Mediate Inhibition of Acetylcholine Release in Cortical Tissue. Nature 1989, 338, 762-763.
8. (a) Ireland, S. J.; Tyers, M. B. Pharmacological Characterization of 5-Hydroxytryptamine-Induced Depolarization of the Rat Isolated Vagus Nerve. Br. J. Pharmacol. 1987, 90, 229-238.
9. (b) Round, A.; Wallis, D. I. Further Studies on the Blockade of 5-HT Depolarizations of Rabbit Vagal Afferent and Sympathetic Ganglion Cells by MDL 72222 and Other Antagonists. Neuro-pharmacology 1987, 26, 39-48.
10. 3 Receptor Ligands and Substance P. J. Neurochem. 1993, 60, 2059-2067.
11. 3 Binding Sites in the Rat Cerebral Cortex and NG 108-15 Clonal Cells. Biochem. Pharmacol. 1990, 40, 1541-1550.
12. 3 Receptor Agonists Based on a Pyrroloquinoxaline Structure. J. Med. Chem. 1997, 40, 3670-3678.
13. 3 Receptor Antagonists Based on the Arylpiperazine Skeleton: Synthesis, Structure, Biological Activity, and Comparative Molecular Field Analysis Studies. J. Med. Chem. 1995, 38, 2692-2704.
14. Compound 5a was reported in a patent by Barber et al. to exhibit antidepressant activity: Barber, H. J.; Jones, D. H. 6-(1-Piperazinyl)phenanthridines. Ger. Patent 1,802,639, 1969; Chem. Abstr. 1969, 71, 49979f.
15. Compound 5a was reported in a patent by Barber et al. to exhibit antidepressant activity: Barber, H. J.; Jones, D. H. 6-(1-Piperazinyl)phenanthridines. Ger. Patent 1,802,639, 1969; Chem. Abstr. 1969, 71, 49979f.
16. 3 Receptor Sites. Med. Chem. Res. 1996, 6, 81-101.
17. i calculation, and other parameters were set in accordance to those described earlier.
18. 3 Receptor Antagonists. Insight into the Interaction with the Receptor. Bioorg. Med. Chem. 1996, 4, 1255-1269.
19. Katritzky, A. R.; Lobanov, V. S.; Karelson, M. QSPR: The Correlation and Quantitative Prediction of Chemical and Physical Properties from Structure. Chem. Soc. Rev. 1995, 279-287.
20. 1-Adrenergic Receptor Ligands. J. Mol. Struct. (THEOCHEM) 1994, 305, 101-110 and references cited therein,
21. 1A Receptor Antagonists. Bioorg. Med. Chem., in press.
22. Ten Hoeve, W.; Kruse, C. G.; Luteyn, J. M.; Thiecke, J. R. G.; Wynberg, H. Direct Substitution of Aromatic Ethers by Lithium Amides. A New Aromatic Amination Reaction. J. Org. Chem. 1993, 58, 5101-5106.
23. Arcus, C. L.; Coombs, M. M.; Evans, J. V. Reactions of Organic Azides. Part V. The Schmidt Reaction with Fluorenones. The Structure of the Intermediate in the Ketonic Schmidt Reaction. J. Chem. Soc. 1956, 1498-1506.
24. Bose, A. K.; Manhas, M. S.; Rao, V. V.; Chen, C. T.; Trehan, I. R.; Sharma, S. D.; Amin, S. G. Heterocyclic Compounds IV. Synthesis of Some Mono- and Diazaphenanthrene Derivatives. J. Heterocycl. Chem. 1971, 8, 1091-1094.
25. White, W. A.; Weingarten, J. J. A Versatile New Enammine Synthesis. J. Org. Chem. 1967, 32, 213-214.
26. Rigby, J. H.; Balasubramanian, N. Preparation of Highly Substituted 2-Pyridones by Reaction of Vinyl Isocyanates and Enamines. J. Org. Chem. 1989, 54, 224-228.
27. Kozikowski, A. P.; Reddy, E. R.; Miller, C. P. A Simplified Route to a Key Intermediate in the Synthesis of the Chinese Nootropic Agent Huperzine A. J. Chem. Soc., Perkin Trans. 1 1990, 195-197.
28. Janin, Y. L.; Bisagni, E. Synthesis of Some Benzo[h]quinoline Derivatives. J. Heterocycl. Chem. 1993, 30, 1129-1131.
29. The imidoyl triflate 14k was isolated and characterized (see Experimental Section).
30. Iwai, I. Polarization of Aromatic Heterocyclic Compounds. XCIV. Benzo[h]quinoline and its Derivatives. J. Pharm. Soc. Jpn. 1951, 71, 1288-1291; Chem. Abstr. 1952, 46, 5587g.
31. Iwai, I. Polarization of Aromatic Heterocyclic Compounds. XCIV. Benzo[h]quinoline and its Derivatives. J. Pharm. Soc. Jpn. 1951, 71, 1288-1291; Chem. Abstr. 1952, 46, 5587g.
32. 1A Serotoninergic Ligands. J. Mol. Struct. (THEOCHEM) 1997, 397, 129-145.
33. QUANTA/CHARMm, 1995, Molecular Simulations Inc., 16 New England Executive Park, Burlington, MA 01803-5297.
34. Dewar, M. J. S.; Zoebisch, E. G.; Healey, E. F.; Stewart, J. J. P. AM1: A New General Purpose Quantum Mechanical Molecular Model. J. Am. Chem. Soc. 1985, 107, 3902-3909.
35. Katritzky, A. R.; Mu, L.; Lobanov, V. S.; Karelson, M. Correlation of Boiling Points with Molecular Structure. 1. A Training Set of 298 Diverse Organics and a Test Set of 9 Simple Inorganics. J. Phys. Chem. 1996, 100, 10400-10407.
36. Karelson, M.; Lobanov, V. S.; Katritzky, A. R. Quantum-Chemical Descriptors in QSAR/QSPR Studies. Chem. Rev. 1996, 96, 1027-1043 and references cited therein.
37. Stanton, D. T.; Jurs, P. C. Development and Use of Charged Partial Surface Area Structural Descriptors in Computer-Assisted Quantitative Structure-Property Relationship Studies. Anal. Chem. 1990, 62, 2323-2329.
38. 3 Binding Sites in Rat Brain Cortical Membranes. Biochem. Pharmacol. 1989, 55, 1693-1695.
39. 3 Serotonin Receptors. J. Med. Chem. 1996, 39, 4017-4026.
40. 3 Receptors. Part 1. Synthesis and Biological Evaluation of Piperazinopyrrolothienopyrazines. J. Med. Chem. 1996, 39, 2068-2080.
41. i values. We are aware that this kind of approach suffers from some limitations (e.g., it assumes that one of the two functional groups compared is inert toward the receptor and no significant difference is present in the conformational and molecular dynamics properties of the compounds; this indeed may appear an oversimplifying assumption); therefore the free energy contributions estimated with this method are used only for comparative purposes. See: Dietrich, S. W.; Bolger, M. B.; Kollman, P. A.; Jorgensen, E C. Thyroxine Analogues. 23. Quantitative Structure-Activity Correlation Studies of in Vivo and in Vitro Thyromimetic Activities. J. Med. Chem. 1977, 20, 863-880.
42. Burley, S. K.; Petsko, G. A. Weakly Polar Interaction in Protein. Adv. Protein Chem. 1988, 39, 125-189.
43. 3 Serotonin Sites. Med. Chem. Res. 1993, 3, 44-51.
44. 3H]8-Hydroxy-2-(di-n-propylamino)tetralin Binding to Pre- and Postsynaptic 5-Hydroxytryptamine Sites in Various Regions of the Rat Brain. J. Neurochem. 1985, 44, 1685-1696.
45. 1c Binding Sites in Rat Frontal Cortex. J. Neurochem. 1986, 47, 529-540.
46. 2 Receptor Sites. Mol. Pharmacol. 1982, 21, 301-314.
47. 3H]Citalopram Binding Proteins. Eur. J. Pharmacol. 1990, 189, 129-134.
48. Meyers, A. I.; Garcia-Munoz, G. The Synthesis of 2-Piridones from Cyclic Cyano Ketones. A New Aromatization Procedure for Dihydro-2-pyridones. J. Org. Chem. 1964, 29, 1435-1438.
49. De Lean, K. W.; Munson, P. J.; Rodbard, D. Simultaneous Analysis of Families of Sigmoidal Curves: Application to Bioassay, Radioligand Assay and Physiological Dose-Response Curves. Am. J. Physiol. 1978, 235, E97-E102.
50. 50) of an Enzymatic Reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.