Synthesis and pharmacology of 6-substituted benztropines: Discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter

Journal of Medicinal Chemistry

Volumn 48, Issue 9, 2005, Pages 3337-3343

  Simoni, Daniele ^a   Rossi, Marcello ^a   Bertolasi, Valerio ^a   Roberti, Marinella ^b   Pizzirani, Daniela ^b   Rondanin, Riccardo ^a   Baruchello, Riccardo ^a   Invidiata, Francesco Paolo ^c   Tolomeo, Manlio ^c   Grimaudo, Stefania ^c   Merighi, Stefania ^a   Varani, Katia ^a   Gessi, Stefania ^a   Borea, Pier Andrea ^a   Marino, Silvia ^a   Cavallini, Sabrina ^a   Bianchi, Clementina ^a   Siniscalchi, Anna ^a  

^a UNIVERSITY OF FERRARA   (Italy)

^b UNIVERSITY OF BOLOGNA   (Italy)

^c UNIVERSITY OF PALERMO   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

3ALPHA [(4 CHLOROPHENYL)PHENYLMETHOXY] 6BETA METHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA [(4 CHLOROPHENYL)PHENYLMETHOXY] 6BETA METHOXYMETHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA [(4 CHLOROPHENYL)PHENYLMETHOXY] 8 METHYL 8 AZABICYCLO[3.2.1]OCTAN 6BETA OL; 3ALPHA [BIS(4 FLUOROPHENYL)METHOXY] 6ALPHA METHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA [BIS(4 FLUOROPHENYL)METHOXY] 6ALPHA METHOXYMETHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA [BIS(4 FLUOROPHENYL)METHOXY] 6BETA METHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA [BIS(4 FLUOROPHENYL)METHOXY] 6BETA METHOXYMETHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA [BIS(4 FLUOROPHENYL)METHOXY] 8 METHYL 8 AZABICYCLO[3.2.1]OCTAN 6ALPHA OL; 3ALPHA [BIS(4 FLUOROPHENYL)METHOXY] 8 METHYL 8 AZABICYCLO[3.2.1]OCTAN 6BETA OL; 3ALPHA DIPHENYLMETHOXY 6BETA METHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA DIPHENYLMETHOXY 6BETA METHOXYMETHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 3ALPHA DIPHENYLMETHOXY 8 METHYL 8 AZABICYCLO[3.2.1] OCTAN 6BETA OL; 6ALPHA [BIS(4 FLUOROPHENYL)METHOXY] 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 6ALPHA METHOXY 3 (4',4'' DIFLUORODIPHENYLMETHOXY)TROPANE; 6BETA [BIS(4 FLUOROPHENYLMETHOXY] 8 METHYL 8 AZABICYCLO[3.2.1]OCTANE; 6BETA METHOXY 8 METHYL 8 AZABICYCLO[3.2.1]OCTAN 3 ONE; 6BETA METHOXYTROPINONE; BENZATROPINE; COCAINE; DOPAMINE; DOPAMINE TRANSPORTER; DOPAMINE UPTAKE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; DOPAMINE UPTAKE; DRUG BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; ENANTIOSELECTIVITY; STRUCTURE ACTIVITY RELATION;

ANIMALS; BENZTROPINE; BINDING, COMPETITIVE; CORPUS STRIATUM; DOPAMINE; DOPAMINE PLASMA MEMBRANE TRANSPORT PROTEINS; DOPAMINE UPTAKE INHIBITORS; MEMBRANE GLYCOPROTEINS; MEMBRANE TRANSPORT PROTEINS; MOLECULAR CONFORMATION; NERVE ENDINGS; NERVE TISSUE PROTEINS; PUTAMEN; RADIOLIGAND ASSAY; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TROPANES;

EID: 20944434890     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0490235     Document Type: Article

References (24)

1. Carrol, F. I.; Howell, L. L.; Kuhar, M. J. Pharmacoterapies for Treatment of Cocaine Abuse: Preclinical Aspects. J. Med. Chem. 1999, 42, 2721-2736, and references therein.
2. Smith, M. P.; Hoepping, A.; Johnson, K. M.; Trzcinska, M.; Kozikowski, A. P. Dopaminergic agents for the treatment of cocaine abuse. Drug. Discovery Today 1999, 4, 322-332, and references therein.
3. Kuhar, M. J.; Ritz, M. C.; Boja, J. W. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci. 1991, 14, 299-301.
4. Madras, B. K.; Miller, G. M.; Meltzer, P. C.; Brownell, A. L.; Fischmann, A. J. Molecular and regional targets of cocaine in primate brain: liberation from prosaic view. Addiction Biol. 2000, 5, 351-359.
5. Newman, A. H.; Kulkarni, S. Probes for dopamine transporter: new leads toward a cocaine-abuse therapeutic: a focus on analogues of benztropine and rimcazol. Med. Res. Rev. 2002, 22, 429-464, and references therein.
6. Meltzer, P. C.; Blundell, P.; Madras, B. K. Structure-activity relationship of inhibition of the dopamine transporter by 3-arylbicyclo[3.2.1] octanes. Med. Chem. Res. 1998, 8, 12-34.
7. Meltzer, P. C.; Wang, B.; Chen, Z.; Blundell, P.; Jayaraman, M.; Gonzales, M. D.; George, C.; Madras, B. K. Synthesis of 6- and 7-hydroxy-8-bicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporter. J. Med. Chem. 2001, 44, 2619-2635.
8. Lomenzo, S. A.; Izenwasser, S.; Katz, J. L.; Terry, P. D.; Zhu, N.; Klein, C. L.; Trudell, M. L. Synthesis, structure, dopamine transporter affinity and dopamine uptake inhibition of 6-alkyl-3-benzyl-2-[(methoxycarbonyl)methyl] tropane derivatives. J. Med. Chem. 1997, 40, 4406-4414.
9. Prakash, K. R. C.; Araldi, G. L.; Smith, M. P.; Zhang, M.; Johnson, K. M.; Kozikowski, A. P. Synthesis and biological activity of new 6- and 7-substituted 2β-butyl-3-phenyltropanes as ligands for the dopamine transporter. Med. Chem. Res. 1998, 8, 43-58.
10. Chen, Z.; Meltzer, P. C. Synthesis of 6- or 7-hydroxy and 6- or 7-methoxy tropanes. Tetrahedron Lett. 1997, 38, 1121-1124.
11. Simoni, D.; Stoelwinder, J.; Kozikowski, A. P.; Johnson, K. M.; Bergmann, J. S.; Ball, R. G. Methoxylation of cocaine reduces binding affinity and produces compounds of differential binding and dopamine uptake inhibitory activity: discovery of a weak cocaine 'antagonist'. J. Med. Chem. 1993, 36, 3975-3977.
12. Simoni, D.; Roberti, M.; Andrisano, M.; Manferdini, M.; Rondanin, R.; Kozikowski, A. P. Concise enantioselective synthesis and attribution of the absolute configuration of two-carbon bridge methoxylated cocaines and pseudococaines. J. Org. Chem. 1998, 63, 4834-4837.
13. Kozikowski, A. P.; Simoni, D.; Manfredini, S.; Roberti, M.; Stoelwinder, J. Synthesis of the 6- and 7-hydroxylated cocaines and pseudococaines. Tetrahedron Lett. 1996, 37, 5333-5336.
14. Meltzer, P. C.; Liang, A. Y.; Madras, B. K. The discovery of an unusually selective and novel cocaine analogue: difluoropine. Synthesis and inhibition of binding at cocaine recognition sites. J. Med. Chem. 1994, 37, 2001-2010.
15. Meltzer, P. C.; Liang, A. Y.; Madras, B. K. 2-Carbomethoxy-3- (diarylmethoxy)-1αH,5αH-tropane analogues: synthesis and inhibition of binding at the dopamine transporter and comparison with piperazine of the GBR series. J. Med. Chem. 1998, 39, 371-379.
16. Van der Zee, P.; Hespe, W. Interaction between substituted 1-[2-(diphenylmethoxy)ethyl] piperazines and dopamine receptors. Neuropharmacology 1985, 24, 1171-1174.
17. Newman, A. H.; Agoston, G. E. Novel benztropine [3α- (diphenylmethoxy)tropane] analogs as probes for the dopamine transporter. Curr. Med. Chem. 1998, 5, 301-315.
18. Newman, A. H.; Robarge, M. J.; Izenwasser, S.; Kline, R. H. A comparative molecular field analysis (CoMFA) study of novel ring substituted 3α-(diphenylmethoxy)tropane analogues at the dopamine transporter. J. Med. Chem. 1999, 42, 3502-3509.
19. Zou, M. F.; Kopajtic, T.; Katz, J. L.; Newman, A. H. Structure-activity relationship of (S)-2β-substituted-3α-(bis[4-fluorophenyl]methoxy) tropanes and (R)-2β-substituted-3β-(3,4-dichlorophenyl)tropanes at the dopamine transporter. J. Med. Chem. 2003, 46, 2908-2916.
20. Zou, M. F.; Agoston, G. E.; Belov, Y.; Kopajtic, T.; Katz, J. L.; Newman, A. H. Enantioselective synthesis of S-(+)-2β-carboalkoxy-3α-[bis(4- fluorophenyl)methoxy]tropanes as novel probes for the dopamine transporter. Bioorg. Med. Chem. Lett. 2002, 12, 1249-1252.
21. Acri, J. B.; Siedleck, B. K.; Witkin, J. M. Effects of benztropine on behavioral and toxic effects of cocaine: comparison with atropine and the selective dopamine uptake inhibitor 1-[2-(diphenylmethoxy)ethyl]-4-(3- phenylpropyl)-piperazine. J. Pharmacol. Exp. Ther. 1996, 277, 198-206.
22. Simoni, D.; Roberti, M.; Rondanin, R.; Baruchello, R.; Rossi, M.; Invidiata, F. P.; Merighi, S.; Varani, K.; Gessi, S.; Borea, P. A.; Marino, S.; Cavallini, S.; Bianchi, C.; Siniscalchi, A. Effects of two-carbon bridge methoxylation of benztropine: discovery of novel chiral ligands for the dopamine transporter. Bioorg. Med. Chem. Lett. 2001, 11, 823-827.
23. Fodor, G.; Soti, F. The stereochemistry of the tropane alkaloids XVII. Correlation of valeroidine with (S)-(-)-methoxysuccinic acid and of mono- and ditigloyltropane-3,6-diol with its (R)-(+)-enantiomer. J. Chem. Soc. 1965, 6830-6833.
24. Grundt, P.; Kopajtic, T. A.; Katz, J. L.; Newman, A. H. The effect of 6-substituted-4′,4″-difluorobenztropine on monoamine transporters and the muscarinic M1 receptor. Bioorg. Med. Chem. Lett. 2004, 14, 3295-3298.