New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo

Journal of Medicinal Chemistry

Volumn 56, Issue 20, 2013, Pages 7851-7861

  Valhondo, Margarita ^a   Marco, Isabel ^a   Martín Fontecha, Mar ^a   Vázquez Villa, Henar ^a   Ramos, José A ^a   Berkels, Reinhard ^b   Lauterbach, Thomas ^b   Benhamú, Bellinda ^a   López Rodríguez, María L ^a  

^a UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^b UCB PHARMA   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

2 [2 [[4 (1,3 DIOXOTETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOL 2(3H) YL)BUTYL]AMINO]ETHOXY]BENZONITRILE; 2 [4 [(2 METHOXYBENZYL)AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [(2 PHENOXYETHYL)AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (1,1' BIPHENYL 2 YLOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (1,1' BIPHENYL 3 YLOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (1,1' BIPHENYL 4 YLOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (2 BROMOPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (2 ETHOXYPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (2 ETHYLPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (2 ISOPROPYLPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (2 METHOXYPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (2 METHOXYPHENYL)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (3 BROMOPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (3 ETHYLPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (3 METHOXYPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (4 BROMOPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (4 ETHYLPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (4 FLUORO 2 METHOXYPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 (4 METHOXYPHENOXY)ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 [2 (TRIFLUOROMETHYL)PHENOXY]ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 [3 (TRIFLUOROMETHYL)PHENOXY]ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[2 [4 (TRIFLUOROMETHYL)PHENOXY]ETHYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[3 (2 METHOXYPHENYL)PROPYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 2 [4 [[4 (2 METHOXYPHENYL)BUTYL]AMINO]BUTYL]TETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOLE 1,3(2H) DIONE; 3 [2 [[4 (1,3 DIOXOTETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOL 2(3H) YL)BUTYL]AMINO]ETHOXY]BENZONITRILE; 4 [2 [[4 (1,3 DIOXOTETRAHYDRO 1H PYRROLO[1,2 C]IMIDAZOL 2(3H) YL)BUTYL]AMINO]ETHOXY]BENZONITRILE; ANALGESIC AGENT; ANTINOCICEPTIVE AGENT; SEROTONIN 1A AGONIST; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANALGESIC ACTIVITY; ANIMAL CELL; ANTINOCICEPTION; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG METABOLISM; DRUG SELECTIVITY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IN VIVO STUDY; LIVER MICROSOME; NONHUMAN; PROTEIN BINDING; RAT;

ANALGESICS; ANIMALS; BINDING, COMPETITIVE; CYCLIC AMP; CYTOCHROME P-450 CYP2D6; HELA CELLS; HETEROCYCLIC COMPOUNDS, 2-RING; HUMANS; HYDANTOINS; KINETICS; LIGANDS; MALE; MICE; MODELS, CHEMICAL; MOLECULAR STRUCTURE; PAIN; PAIN MEASUREMENT; PIPERAZINES; PYRIDINES; RADIOLIGAND ASSAY; RATS; RECEPTOR, SEROTONIN, 5-HT1A; SEROTONIN 5-HT1 RECEPTOR AGONISTS; SEROTONIN ANTAGONISTS;

EID: 84886517382     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400766k     Document Type: Article

References (45)

1. Nichols, D. E.; Nichols, C. D. Serotonin receptors Chem. Rev. 2008, 108, 1614-1641
2. 1A receptor Nature 1988, 335, 358-360
3. 1A receptors Curr. Med. Chem. 2002, 9, 443-469
4. Caliendo, G.; Santagada, V.; Perissutti, E.; Fiorino, F. Derivatives as 5-HT(1A) receptor ligands: Past and present Curr. Med. Chem. 2005, 12, 1721-1753
5. 1A receptor, an old target for new therapeutic agents Curr. Top. Med. Chem. 2008, 8, 1024-1034
6. 1A receptors in the treatment of schizophrenia and Parkinson's disease CNS Neurosci. Ther. 2011, 17, 58-65
7. 1A receptors: A patent review Expert Opin. Ther. Pat. 2012, 22, 887-902
8. 1A receptor ligands in animal-models of anxiety, impulsivity and depression: Multiple mechanisms of action Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1993, 17, 87-104
9. 1A agonists in the treatment of depression? Biol. Psychiatry 2003, 53, 193-203
10. 1A receptor function in major depressive disorder Prog. Neurobiol. 2009, 88, 17-31
11. 1A receptor in schizophrenia: A promising target for novel atypical neuroleptics? J. Psychopharmacol. 2001, 15, 37-46
12. 1A receptor agonist Pharmacology 2001, 62, 234-242
13. 3 receptors Eur. J. Pharmacol. 2005, 511, 9-19
14. 1A receptor agonism Curr. Pharm. Des. 2010, 16, 516-521
15. 1A receptor agonist J. Med. Chem. 2010, 53, 1319-1328
16. Madhavan, L.; Freed, W. J.; Anantharam, V.; Kanthasamy, A. G. 5-Hydroxytryptamine 1A receptor activation protects against N -methyl- d -aspartate-induced apoptotic cell death in striatal and mesencephalic cultures J. Pharmacol. Exp. Ther. 2003, 304, 913-923
17. 1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke CNS Drug Rev. 2005, 11, 379-402
18. Chang, C. P.; Chen, S. H.; Lin, M. T. Ipsapirone and ketanserin protects against circulatory shock, intracranial hypertension, and cerebral ischemia during heatstroke Shock 2005, 24, 336-340
19. 1A receptor agonist, is well tolerated in patients with acute stroke Stroke 2006, 37, 655-655
20. 1A receptor agonists with neuroprotective effect: Discovery of piclozotan Bioorg. Med. Chem. 2006, 14, 1978-1992
21. Teal, P.; Davis, S.; Hacke, W.; Kaste, M.; Lyden, P. D.; Fierus, M. A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke modified randomized exposure controlled trial Stroke 2009, 40, 3518-3525
22. 1A receptor agonists with neuroprotective effect against ischemic cell damage J. Med. Chem. 2011, 54, 7986-7999
23. 1A agonist in advanced Parkinson's disease Mov. Disord. 2005, 20, 932-936
24. Fox, S. H.; Chuang, R.; Brotchie, J. M. Serotonin and Parkinson's disease: On movement, mood, and madness Mov. Disord. 2009, 24, 1255-1266
25. 1A receptors in research strategy for extensive pain treatment Curr. Top. Med. Chem. 2006, 6, 1997-2003
26. 1A receptor activation: A new mechanism of profound, central analgesia Neuropharmacology 2002, 43, 945-958
27. 1A receptor activation: New molecular and neuroadaptive mechanisms of pain relief Curr. Opin. Invest. Drugs 2006, 7, 40-47
28. 1A agonist F 13640 in the formalin model of tonic nociceptive pain Pharmacology 2003, 67, 182-194
29. Bang-Andersen, B.; Faldt, A.; Moerk, A.; Lopez De Diego, H.; Holm, R.; Stensboel, T. B.; Ringgaard, L. M.; Mealy, M. J.; Rock, M. H.; Brodersen, J.; Joergensen, M.; Moore, N. PCT/DK2007/050075, WO 2007/144005 A1, 2007.
30. Moore, N.; Stensboel, T. B. PCT/DK2008/050063, WO 2008/113359 A2, 2008.
31. https://www.clinicaltrialsregister.eu/ctr-search/search?query= F13640+and+pain.
32. 1A receptor agonist J. Med. Chem. 1996, 39, 4439-4450
33. 1A affinity/selectivity J. Med. Chem. 1997, 40, 2653-2656
34. 2 antagonist properties J. Med. Chem. 2001, 44, 186-197
35. 1-adrenergic receptor affinity by classical Hansch analysis, artificial neural networks, and computational simulation of ligand recognition J. Med. Chem. 2001, 44, 198-207
36. 1A affinity/selectivity Bioorg. Med. Chem. 2004, 12, 1551-1557
37. 1-adrenoceptors J. Med. Chem. 2005, 48, 2548-2558
38. Lopez-Rodriguez, M. L.; Benhamu, B.; del Rio, J.; Frechilla, D.; Marco, I. PCT/EP2005/000840, WO 2005/075480 A1, 2005.
39. Stohr, T.; Lopez-Rodriguez, M. L.; Benhamu, B. PCT/IB2007/002194, WO2008/015538 A2, 2008.
40. 50) of an enzymatic reaction Biochem. Pharmacol. 1973, 22, 3099-3108
41. Obach, R. S.; Baxter, J. G.; Liston, T. E.; Silber, B. M.; Jones, B. C.; MacIntyre, F.; Rance, D. J.; Wastall, P. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data J. Pharmacol. Exp. Ther. 1997, 283, 46-58
42. Vissers, K. C. P.; Geenen, F.; Biermans, R.; Meert, T. F. Pharmacological correlation between the formalin test and the neuropathic pain behavior in different species with chronic constriction injury Pharmacol., Biochem. Behav. 2006, 84, 479-486
43. Pan, H.-L.; Wu, Z.-Z.; Zhou, H.-Y.; Chen, S.-R.; Zhang, H.-M.; Li, D.-P. Modulation of pain transmission by G-protein-coupled receptors Pharmacol. Ther. 2008, 117, 141-161
44. Dakin, H. D. Amino acids of gelatin J. Biol. Chem. 1920, 44, 499-529
45. Hunskaar, S.; Fasmer, O. B.; Hole, K. Formalin test in mice, a useful technique for evaluating mild analgesics J. Neurosci. Methods 1985, 14, 69-76