Dopamine Transport Inhibitors Based on GBR12909 and Benztropine As Potential Medications to Treat Cocaine Addiction

Overview

Journal Biochem Pharmacol

Specialties Biochemistry
Pharmacology

Date 2007 Sep 28

PMID 17897630

Citations 48

Authors

Richard B Rothman

Michael H Baumann

Thomas E Prisinzano

Amy Hauck Newman

Affiliations

Soon will be listed here.

Abstract

The discovery and development of medications to treat addiction and notably, cocaine addiction, have been frustrated by both the complexity of the disorder and the lack of target validation in human subjects. The dopamine transporter has historically been a primary target for cocaine abuse medication development, but addictive liability and other confounds of such inhibitors of dopamine uptake have limited clinical evaluation and validation. Herein we describe efforts to develop analogues of the dopamine uptake inhibitors GBR 12909 and benztropine that show promising profiles in animal models of cocaine abuse that contrast to that of cocaine. Their unique pharmacological profiles have provided important insights into the reinforcing actions of cocaine and we propose that clinical investigation of novel dopamine uptake inhibitors will facilitate the discovery of cocaine-abuse medications.

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References

Baumann M, Rothman R . Alterations in serotonergic responsiveness during cocaine withdrawal in rats: similarities to major depression in humans. Biol Psychiatry. 1998; 44(7):578-91. DOI: 10.1016/s0006-3223(98)00123-1. View

Newman A, Kulkarni S . Probes for the dopamine transporter: new leads toward a cocaine-abuse therapeutic--A focus on analogues of benztropine and rimcazole. Med Res Rev. 2002; 22(5):429-64. DOI: 10.1002/med.10014. View

Newman A, Kline R, Allen A, Izenwasser S, George C, Katz J . Novel 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors. J Med Chem. 1995; 38(20):3933-40. DOI: 10.1021/jm00020a006. View

Skjoldager P, Winger G, Woods J . Effects of GBR 12909 and cocaine on cocaine-maintained behavior in rhesus monkeys. Drug Alcohol Depend. 1993; 33(1):31-9. DOI: 10.1016/0376-8716(93)90031-k. View

Andersen P . Biochemical and pharmacological characterization of [3H]GBR 12935 binding in vitro to rat striatal membranes: labeling of the dopamine uptake complex. J Neurochem. 1987; 48(6):1887-96. DOI: 10.1111/j.1471-4159.1987.tb05752.x. View

Katz J, Newman A, Izenwasser S . Relations between heterogeneity of dopamine transporter binding and function and the behavioral pharmacology of cocaine. Pharmacol Biochem Behav. 1997; 57(3):505-12. DOI: 10.1016/s0091-3057(96)00441-8. View

Katz J, Kopajtic T, Agoston G, Newman A . Effects of N-substituted analogs of benztropine: diminished cocaine-like effects in dopamine transporter ligands. J Pharmacol Exp Ther. 2004; 309(2):650-60. DOI: 10.1124/jpet.103.060525. View

Howell L, Wilcox K . The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates. J Pharmacol Exp Ther. 2001; 298(1):1-6. View

Kulkarni S, Grundt P, Kopajtic T, Katz J, Newman A . Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation. J Med Chem. 2004; 47(13):3388-98. DOI: 10.1021/jm030646c. View

10.

Agoston G, Wu J, Izenwasser S, George C, Katz J, Kline R . Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. J Med Chem. 1998; 40(26):4329-39. DOI: 10.1021/jm970525a. View

11.

Robarge M, Agoston G, Izenwasser S, Kopajtic T, George C, Katz J . Highly selective chiral N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues for the dopamine transporter: synthesis and comparative molecular field analysis. J Med Chem. 2000; 43(6):1085-93. DOI: 10.1021/jm990265s. View

12.

Katz J, Izenwasser S, Kline R, Allen A, Newman A . Novel 3alpha-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine. J Pharmacol Exp Ther. 1998; 288(1):302-15. View

13.

Tanda G, Ebbs A, Kopajtic T, Elias L, Campbell B, Newman A . Effects of muscarinic M1 receptor blockade on cocaine-induced elevations of brain dopamine levels and locomotor behavior in rats. J Pharmacol Exp Ther. 2007; 321(1):334-44. DOI: 10.1124/jpet.106.118067. View

14.

Vocci F, Acri J, Elkashef A . Medication development for addictive disorders: the state of the science. Am J Psychiatry. 2005; 162(8):1432-40. DOI: 10.1176/appi.ajp.162.8.1432. View

15.

Hirate K, Kuribara H . Characteristics of the ambulation-increasing effect of GBR-12909, a selective dopamine uptake inhibitor, in mice. Jpn J Pharmacol. 1991; 55(4):501-11. DOI: 10.1254/jjp.55.501. View

16.

Nestler E . Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2001; 2(2):119-28. DOI: 10.1038/35053570. View

17.

Campbell V, Kopajtic T, Newman A, Katz J . Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs. J Pharmacol Exp Ther. 2005; 315(2):631-40. DOI: 10.1124/jpet.105.090829. View

18.

Villemagne V, Rothman R, Yokoi F, Rice K, Matecka D, Dannals R . Doses of GBR12909 that suppress cocaine self-administration in non-human primates substantially occupy dopamine transporters as measured by [11C] WIN35,428 PET scans. Synapse. 1999; 32(1):44-50. DOI: 10.1002/(SICI)1098-2396(199904)32:1<44::AID-SYN6>3.0.CO;2-9. View

19.

Baumann M, Phillips J, Ayestas M, Ali S, Rice K, Rothman R . Preclinical evaluation of GBR12909 decanoate as a long-acting medication for methamphetamine dependence. Ann N Y Acad Sci. 2002; 965:92-108. DOI: 10.1111/j.1749-6632.2002.tb04154.x. View

20.

Newman A, Allen A, Izenwasser S, Katz J . Novel 3 alpha-(diphenylmethoxy)tropane analogs: potent dopamine uptake inhibitors without cocaine-like behavioral profiles. J Med Chem. 1994; 37(15):2258-61. DOI: 10.1021/jm00041a002. View