Synthesis and evaluation of a set of 4-Phenylpiperidines and 4-Phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(Methylsulfonyl)phenyl]-l-propylpiperidine (huntexil, pridopidine, ACR16)

Journal of Medicinal Chemistry

Volumn 53, Issue 6, 2010, Pages 2510-2520

  Pettersson, Fredrik ^a   Ponten, Henrik ^a   Waters, Nicholas ^a   Waters, Susanna ^a   Sonesson, Clas ^a  

^a NeuroSearch Sweden AB   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

1 PHENYLPIPERAZINE DERIVATIVE; 3,4 DIHYDROXYPHENYLACETIC ACID; 4 PHENYLPIPERIDINE DERIVATIVE; AMPHETAMINE; APOMORPHINE; ARIPIPRAZOLE; BIFEPRUNOX; DOPAMINE; DOPAMINE 2 RECEPTOR; DOPAMINE RECEPTOR BLOCKING AGENT; DOPAMINE RECEPTOR STIMULATING AGENT; HALOPERIDOL; HUNTEXIL; OLANZAPINE; PHENOL DERIVATIVE; PRECLAMOL; PRIDOPIDINE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CELL STRAIN HEK293; CONTROLLED STUDY; CORPUS STRIATUM; DOPAMINE RECEPTOR BLOCKING; DOPAMINERGIC ACTIVITY; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SYNTHESIS; HABITUATION; HUMAN; HUMAN CELL; HYPERACTIVITY; IN VITRO STUDY; IN VIVO STUDY; LOCOMOTION; NONHUMAN; RAT; RECEPTOR AFFINITY; RECEPTOR INTRINSIC ACTIVITY; STRUCTURE ACTIVITY RELATION; TISSUE LEVEL;

3,4-DIHYDROXYPHENYLACETIC ACID; ANIMALS; BINDING, COMPETITIVE; CELL LINE; CORPUS STRIATUM; DOPAMINE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; HUMANS; LIGANDS; MALE; MODELS, CHEMICAL; MOLECULAR STRUCTURE; MOTOR ACTIVITY; PIPERAZINES; PIPERIDINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, DOPAMINE D2;

EID: 77949834466     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm901689v     Document Type: Article

References (66)

1. Johnson, G. L.; Dhanasekaran, N. The G-protein family and their interaction with receptors. Endocr. Rev. 1989, 10, 317-331.
2. Seeman, P. Atypical antipsychotics: mechanism of action. Can. J. Psychiatry 2002, 47, 27-38.
3. Seeman, P. An Update of Fast-Off Dopamine D2 Atypical Antipsychotics. Am. J. Psychiatry 2005, 162, 1984-1985.
4. George, S. R.; Watanabe, M.; Di Paolo, T.; Falardeau, P; Labrie, F.; Seeman, P. The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form. Endocrinology 1985, 117, 690-697.
5. Sibley, D. R.; De Lean, A.; Creese, I. Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor. J. Biol. Chem. 1982, 257, 6351-6361.
6. Payne, S. L.; Johansson, A. M.; Strange, P. G. Mechanisms of ligand binding and efficacy at the human D2(short) dopamine receptor. J. Neurochem. 2002, 82, 1106-1117.
7. 3H]raclopride or [ H]spiperone in isotonic medium: implications for human positron emission tomography. Synapse 2003, 49, 209-215.
8. Kenakin, T. Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol. Sci. 2007, 28, 401-415.
9. Lahti, R. A.; Figur, L. M.; Piercey, M. F.; Ruppel, P. L.; Evans, D. L. Intrinsic activity determinations at the dopamine D2 guanine nucleotide-binding protein-coupled receptor: utilization of receptor state binding affinities. Mol. Pharmacol. 1992, 42, 432-439.
10. Malmberg, Å.; Mohella, N.; Backlund Höök, B.; Johansson, A. M.; Hacksell, U.; Nordvall, G. Interactions of ligands with active and inactive conformations of the dopamine D2 receptor. Eur. J. Pharmacol. 1998, 346, 299-307.
11. Mewshaw, R. E.; Kavanagh, J.; Stack, G.; Marquis, K. L.; Shi, X.; Kagan, M. Z.; Webb, M. B.; Katz, A. H.; Park, A.; Kang, Y. H.; Abou-Gharbia, M.; Scerni, R.; Wasik, T.; Cortes-Burgos, L.; Spangler, T.; Brennan, J. A.; Piesla, M.; Mazandarani, H.; Cockett, M. I.; Ochalski, R.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans. J. Med. Chem. 1997, 40, 4235-4256.
12. Clark, D.; Hjort, S.; Carlsson, A. Dopamine receptor agonists: mechanisms underlying autoreceptor selectivity II. Theoretical considerations. J. Neural Transm. 1985, 62, 171-207.
13. Casey, D. E.; Keepers, G. A. Neuroleptic side effects: acute extrapyramidal syndromes and tardive dyskinesia. Psychopharmacol. Ser. 1988, 5, 74-93.
14. Lahti, A. C.; Weiler, M. A.; Corey, P. K.; Lahti, R. A.; Carlsson, A.; Tamminga, C. A. Antipsychotic properties of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (preclamol) in schizophrenia. Biol. Psychiatry 1998, 43, 2-11.
15. Petrie, J. L.; Saha, A. R.; McEvoy, J. P. Aripiprazole, a new atypical antipsychotic: phase II clinical trial results. Eur. Neuropsychopharmacol. 1997, 7, 227.
16. Carlsson, A.; Tamminga, C. A. Partial dopamine agonists and dopaminergic stabilizers, in the treatment of psychosis. Curr. Drug Targets: CNS Neurol. Disord. 2002, 1, 141-147.
17. Broadley, K. J.; Kelly, D. R. Muscarinic receptor agonists and antagonists. Molecules 2001, 5, 142-193.
18. Esbenshade, T. A.; Fox, G. B.; Cowart, M. D. Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders. Mol. Interventions 2006, 5, 77-88.
19. Gualtieri, F. Cholinergic receptors and neurodegenerative diseases. Pharm. Acta Helv. 2000, 74, 85-89.
20. Kubinyi, H. Chemical similarity and biological activites. J. Braz. Chem. Soc. 2002, 13, 717-726.
21. Smith, J. H. Introduction to the Principles of Drug Design and Action, 3rd ed.; Harwood Academic Publishers: London, 1998; pp 387-433.
22. Parker, M. A.; Kurrasch, D. M.; Nichols, D. E. The role of lipophilicity in determining binding affinity and functional activity for 5-HT2A receptor ligands. Bioorg. Med. Chem. 2008, 16, 4661-4669.
23. Runyon, S. P.; Mosier, P. D.; Roth, B. L.; Glennon, R. A.; Westkaemper, R. B. Potential modes of interaction of 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives with the 5-HT2A receptor: a ligand structure-affinity relationship, receptor mutagenesis and receptor modeling investigation. J. Med. Chem. 2008, 51, 6808-6828.
24. Ariens, E. J. Drug Design; Academic Press: New York, 1971; Vol.1, pp 162-193.
25. Hansch, C.; Leo, A. Substituent Constants for Correlation Analysis in Chemistry and Biology; Wiley: New York, 1979.
26. Cho, W.; Taylor, L. P.; Mansour, A.; Akil, H. Hydrophobic residues of the D2 dopamine receptor are important for binding and signal transduction. J. Neurochem. 1995, 65, 2105-2215.
27. Cox, B. A.; Henningsen, R. A.; Spanoyannis, A.; Neve, R. L.; Neve, K. A. Contributions of conserved serine residues to the interactions of ligands with dopamine D2 receptors. J. Neurochem. 1992, 59, 627-635.
28. Mansour, A.; Meng, F.; Meador-Woodruff, J. H.; Taylor, L. P.; Qvelli, O.; Akil, H. Site-directed mutagenesis of the human dopamine D2 receptor. Eur. J. Pharmacol. 1992, 227, 205-214.
29. Shi, L.; Javitch, J. A. The binding site of aminergic G proteincoupled receptors: the transmembrane segments and second extracellular loop. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 437-467.
30. Teeter, M. M.; Froimowitz, M.; Stec, B.; DuRand, C. J. Homology modeling of the dopamine D2 receptor and its testing by docking of agonists and tricyclic antagonists. J. Med. Chem. 1994, 37, 2874-2888.
31. Wiens, B. L.; Nelson, C. S.; Neve, K. A. Contribution of serine residues to constitutive and agonist-induced signaling via the D2S dopamine receptor: evidence for multiple, agonist-specific active conformations. Mol. Pharmacol. 1998, 54, 435-444.
32. Wilcox, R. E.; Huang, W.-H.; Brusniak, M.-Y. K.; Wilcox, D. M.; Pearlman, R. S.; Teeter, M. M.; DuRand, C. J.; Wiens, B. L.; Neve, K. A. CoMFA-based prediction of agonist affinities at recombinant wild type versus serine to alanine point mutated D2 dopamine receptors. J. Med. Chem. 2000, 43, 3005-3019.
33. Yashar, M.; Kalani, S.; Vaidehi, N.; Hall, S. E.; Trabanino, R. J.; Freddolino, P. L.; Kalani, M. A.; Floriano, W. B.; Tak Kam, V. W.; Goddard, W. A., III. The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 3815-3820.
34. Vilardaga, J.-P. Switching modes for G protein-coupled receptor activation. Nat. Chem. 2006, 2, 395-396.
35. Ballesteros, J. A.; Jensen, A. D.; Liapakis, G.; Rasmussen, S.; Shi, L.; Gether, U.; Javitch, J. A. Activation of the 2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J. Biol. Chem. 2001, 276, 29171-29177.
36. Hubbell, W. L.; Altenbach, C.; Hubbell, C. M.; Khorana, H. G. Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydry1 reactivity, and disulfide cross-linking. Adv. Protein Chem. 2003, 63, 243-290.
37. Yao, X.; Parnot, C.; Deupi, X.; Ratnala, V. R. P.; Swaminath, G.; Farrens, D.; Kobilka, B. Coupling ligand structure to specific conformational switches in the beta(2)-adrenoceptor. Nat. Chem. Biol. 2006, 2, 417-422.
38. Goddard, W. A., III; Abrol, R. 3-Dimensional structure of G protein-coupled receptors and binding sites of agonists and antagonists. J. Nutr. 2007, 137, 1528-1538.
39. Dowd, C. S.; Herrick-Davis, K.; Egan, C.; DuPre, A.; Smith, C.; Teitler, M.; Glennon, R. A. 1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT2A partial agonists. J. Med. Chem. 2000, 43, 3074-3084.
40. Seggel, M. R.; Yousif, M. Y.; Lyon, R. A.; Titeler, M.; Roth, B. L.; Suba, E. A.; Glennon, R. A. A structure-affinity study of the binding of 4-substituted analogues of l-(2,5-dimethoxyphenyl)-2-aminopropanaet 5-HT2 serotonin receptors. J. Med. Chem. 1990, 33, 1032-1036.
41. Assié, M. B.; Koek, W. Effects of 5-HT1A receptor antagonists on hippocampal 5-hydroxytryptamine levels: (S)-WAY100135, but not WAY100635, has partial agonist properties. Eur. J. Pharmacol. 1996, 304, 15-21.
42. Mattsson, C.; Sonesson, C.; Sandahl, A.; Greiner, H. E.; Gassen, M.; Plaschke, J.; Leibrock, J.; Bottcher, H. 2-Alkyl-3-(l,2,3,6-tetrahydropyridin-4- yl)-1 H-indoles as novel 5-HT6 receptor agonists. Bioorg. Med. Chem. Lett. 2005, 15, 4230-4234.
43. Clark, D.; Hjort, S.; Carlsson, A. Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. J. Neural Transm. 1985, 62, 1-52.
44. Sonesson, C.; Waters, N.; Svensson, K.; Carlsson, A.; Smith, M. W.; Piercey, M. F.; Meier, E.; Wikström, H. Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists. J. Med. Chem. 1993, 36, 3188-3196.
45. Sonesson, C.; Lin, C.-H.; Hansson, L.; Waters, N.; Svensson, K.; Carlsson, A.; Smith, M. W.; Wikström, H. Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: synthesis and structure-activity relationships. J. Med. Chem. 1994, 37, 2735-2753.
46. Carlsson, M. L.; Nilsson, M.; Carlsson, A. Schizophrenia: from dopamine to glutamate and back. Curr. Med. Chem. 2004, 11, 267-277.
47. Natesan, S.; Svensson, K. A.; Reckless, G. E.; Nobrega, J. N.; Barlow, K. B. L.; Johansson, A. M.; Kapur, S. The dopamine stabilizers (S)-(-)-(3-methanesulfonyl-phenyl)-l-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACRl 6) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat. J. Pharmacol. Exp. Ther. 2006, 318, 810-818.
48. Seeman, P.; Guan, H. C. Dopamine partial agonist action of (-)-OSU6162 is consistent with dopamine hyperactivity in psychosis. Eur. J. Pharmacol. 2006, 557, 151-153.
49. Lahti, R. A.; Tamminga, C. A.; Carlsson, A. Stimulating and inhibitory effects of the dopamine "stabilizer" (-)-OSU6162 on dopamine D2 receptor function in vitro. J. Neural Transm. 2007, 114, 1143-1146.
50. Dyhring, T.; Nielsen, E. O.; Sonesson, C.; Pettersson, F.; Karlsson, J.; Svensson, P.; Christophersen, P.; Waters, N. The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D2 receptor antagonism and fast receptor dissociation properties. Eur. J. Pharmacol. 2010, 628 (1-3), 19-26.
51. McGaughey, G. B.; Mewshaw, R. E. Application of comparative molecular field analysis to dopamine D2 partial agonists. Bioorg. Med. Chem. Lett. 1999, 7, 2453-2456.
52. 1-phenylpiperazine. Bioorg. Med. Chem. Lett. 1998, 8, 295-300.
53. Bartholomew, C. H.; Agrawal, P. K.; Katzer, J. R. Sulphur poisoning of metals. Adv. Catal. 1982, 31, 135-242.
54. Burris, K. D.; Molski, T. F.; Xu, C.; Ryan, E.; Tottori, K.; Kikuchi, T.; Yocca, F.D.; Molinoff, P. B. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J. Pharmacol. Exp. Ther. 2002, 302, 381-389.
55. Tadori, Y.; Miwa, T.; Tottori, K.; Burris, K. D.; Stark, A.; Mori, T.; Kikuchi, T. Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic. Eur. J. Pharmacol. 2005, 515, 10-19.
56. Tadori, Y.; Kitagawa, H.; Forbes, R. A.; McQuade, R. D.; Stark, A.; Kikuchi, T. Differences in agonist/antagonist properties at human dopamine D2 receptors between aripiprazole, bifeprunox and SDZ 208-912. Eur. J. Pharmacol. 2007, 574, 103-111.
57. Hacksell, U.; Arvidsson, L. E.; Svensson, U.; Nilsson, J. L. G.; Sanchez, D.; Wikstroem, H.; Lindberg, P.; Hjorth, S.; Carlsson, A. 3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity. J. Med. Chem. 1981, 24, 1475-1482.
58. Dijkstra, G. D. H. Conformational analysis of 1-arylpiperazines and 4-arylpiperidines. Rec. Trav. Chim. Pays-Bas 1993, 112, 151-160.
59. McGaughey, G. B.; Mewshaw, R. E. Molecular Modeling and the Design of Dopamine D2 Partial Agonists, http://www.netsci.org/Science/Compchem/feature20. html.
60. Caffieri, S. Reversed-phase high-performance liquid chromatography (RP-HPLC) determination of lipophilicity of furocoumarins: relationship with DNA interaction. J. Pharm. Sci. 2001, 90, 732-739.
61. Leopoldo, M.; Lacivita, E.; De Giorgio, P.; Fracasso, C.; Guzzetti, S.; Caceia, S.; Contino, M.; Colabufo, N. A.; Berardi, F.; Perrone, R. Structural modifications of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-l- piperazinehexanamides: influence on lipophilicity and 5-HT7 receptor activity. Part III. J. Med. Chem. 2008, 51, 5813-5822.
62. ACD/Labs, version 10; Advanced Chemistry Devlopment, Inc.: Toronto, Ontario, Canada, 2007.
63. a values: the substituent on aryl modulates basicity. Bioorg. Med. Chem. 2009, 17, 1339-1344.
64. Rung, J. P.; Rung, E.; Helgeson, L.; Johansson, A. M.; Svensson, K.; Carlsson, A.; Carlsson, M. L. Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization. J. Neural Transm. 2008, 115, 899-908.
65. Carlsson, A.; Carlsson, M. L. A dopaminergic deficit hypothesis of schizophrenia: the path to discovery. Dial. Clin. Neurosa. 2006, 8, 137-142.
66. Seeman, P.; Tokita, K.; Matsumoto, M.; Matsuo, A.; Sasamata, M.; Miyata, K. D. The dopaminergic stabilizer ASP2314/ACR16 selectively interacts with D2High receptors. Synapse 2009, 8, 930-934.