N-substituted benztropine analogs: Selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects

Journal of Pharmacology and Experimental Therapeutics

Volumn 336, Issue 2, 2011, Pages 575-585

  Li, Su Min ^a   Kopajtic, Theresa A ^a   O'Callaghan, Matthew J ^a,b   Agoston, Gregory E ^a,c   Cao, Jianjing ^a   Newman, Amy Hauck ^a   Katz, Jonathan L ^a  

^a NATIONAL INSTITUTE ON DRUG ABUSE   (United States)

^b UNIVERSITY OF ABERDEEN   (United Kingdom)

^c UNITED STATES PHARMACOPEIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZATROPINE; COCAINE; DOPAMINE TRANSPORTER; GA 1 69; GA 2 50; GA 2 99; JHW 013; MUSCARINIC M1 RECEPTOR; NORADRENALIN; SEROTONIN; SEROTONIN TRANSPORTER; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; DOSE RESPONSE; DRUG ABUSE; DRUG EFFECT; DRUG RECEPTOR BINDING; DRUG STRUCTURE; LOCOMOTION; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT;

ANIMALS; BEHAVIOR, ANIMAL; BENZTROPINE; COCAINE; CONDITIONING (PSYCHOLOGY); DISCRIMINATION LEARNING; DOPAMINE PLASMA MEMBRANE TRANSPORT PROTEINS; DOSE-RESPONSE RELATIONSHIP, DRUG; GUINEA PIGS; LIGANDS; MALE; MOTOR ACTIVITY; RATS; RATS, SPRAGUE-DAWLEY; SELF ADMINISTRATION;

EID: 78751474117     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.110.173260     Document Type: Article

References (38)

1. Agoston GE, Wu JH, Izenwasser S, George C, Katz J, Kline RH, and Newman AH (1997) Novel N-substituted-3α-[bis (4′fluorophenyl methoxy)] tropane analogues: selective ligands for the dopamine transporter. J Med Chem 40:4329-4339.
2. Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, Newman AH, Javitch JA, Weinstein H, Gether U, et al. (2008) The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci 11:780-789.
3. 2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem 6:1971-1985.
4. Campbell VC, Kopajtic TA, Newman AH, and Katz JL (2005) Assessment of the influence of histaminergic actions on cocaine-like effects of 3α-diphenylmethoxytropane analogues. J Pharmacol Exp Ther 315:631-640.
5. Chausmer AL, Elmer GI, Rubinstein M, Low MJ, Grandy DK, and Katz JL (2002) Cocaine-induced locomotor activity and cocaine discrimination in dopamine D2 receptor mutant mice. Psychopharmacology 163:54-61.
6. 50) of an enzymatic reaction. Biochem Pharmacol 22:3099-3108.
7. De Beun R, Jansen E, Geerts NE, Slangen JL, and Van de Poll NE (1992) Temporal characteristics of appetitive stimulus effects of luteinizing hormone-releasing hormone in male rats. Pharmacol Biochem Behav 42:445-450.
8. Desai RI, Kopajtic TA, French D, Newman AH, and Katz JL (2005a) Relationship between in vivo occupancy at the dopamine transporter and behavioral effects of cocaine, GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy] ethyl}-4-(3-phenylpropyl) piperazine]and benztropine analogs. J Pharmacol Exp Ther 315:397-404.
9. Desai RI, Kopajtic TA, Koffarnus M, Newman AH, and Katz JL (2005b) Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine. J Neurosci 25:1889-1893.
10. Ferragud A, Velázquez-Sánchez C, Hernández-Rabaza V, Nácher A, Merino V, Cardá M, Murga J, and Canales JJ (2009) A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat. Psychopharmacology 207:281-289.
11. Hiranita T, Kopajtic T, Newman AH, and Katz JL (2009a) Regulation of cocaine self-administration in rats by sigma (σ) receptors, in Neuroscience Meeting Planner; 2009 Oct 17-21; Chicago, IL. Program 496.1. Society for Neuroscience, Washington, DC.
12. Hiranita T, Soto PL, Newman AH, and Katz JL (2009b) Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors. J Pharmacol Exp Ther 329:677-686.
13. Hiranita T, Soto PL, Tanda G, and Katz JL (2010) Reinforcing effects of σ-receptor agonists in rats trained to self-administer cocaine. J Pharmacol Exp Ther 332:515-524.
14. Katz JL, Izenwasser S, Kline RH, Allen AC, and Newman AH (1999) Novel 3α-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine. J Pharmacol Exp Ther 288:302-315.
15. Katz JL, Kopajtic TA, Agoston GE, and Newman AH (2004) Effects of N-substituted analogs of benztropine: diminished cocaine-like effects in dopamine transporter ligands. J Pharmacol Exp Ther 309:650-660.
16. Katz JL, Libby TA, Kopajtic T, Husbands SM, and Newman AH (2003) Behavioral effects of rimcazole analogues alone and in combination with cocaine. Eur J Pharmacol 468:109-119. (Pubitemid 36556254)
17. Kelly MA, Rubinstein M, Phillips TJ, Lessov CN, Burkhart-Kasch S, Zhang G, Bunzow JR, Fang Y, Gerhardt GA, Grandy DK, et al. (1998) Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci 18:3470-3479. (Pubitemid 28186038)
18. Kopajtic TA, Liu Y, Surratt CK, Donovan DM, Newman AH, and Katz JL (2010) Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability. J Pharmacol Exp Ther 335:703-714.
19. Kuhar MJ, Ritz MC, and Boja JW (1991) The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 14:299-302.
20. Kulkarni SS, Grundt P, Kopajtic T, Katz JL, and Newman AH (2004) Structure-activity relationships at monoamine transporters for a series of N-substituted 3α-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation. J Med Chem 47:3388-3398. (Pubitemid 38746090)
21. Li SM, Newman AH, and Katz JL (2005) Place conditioning and locomotor effects of N-substituted, 4′,4″-difluorobenztropine analogs in rats. J Pharmacol Exp Ther 313:1223-1230.
22. Li SM, Yin LL, Shi J, Lin ZB, and Zheng JW (2002) The effect of 7-nitroindazole on the acquisition and expression of D-methamphetamine-induced place preference in rats. Eur J Pharmacol 435:217-223.
23. Loland CJ, Desai RI, Zou MF, Cao J, Grundt P, Gerstbrein K, Sitte HH, Newman AH, Katz JL, and Gether U (2008) Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Mol Pharmacol 73:813-823.
24. Loland CJ, Norregaard L, Litman T, and Gether U (2002) Generation of an activating Zn(2+) switch in the dopamine transporter: mutation of an intracellular tyrosine constitutively alters the conformational equilibrium of the transport cycle. Proc Natl Acad Sci USA 99:1683-1688.
25. Matsumoto RR (2009) Targeting sigma receptors: novel medication development for drug abuse and addiction. Exp Rev Clin Pharmacol 2:351-358.
26. Navarro HA, Howard JL, Pollard GT, and Carroll FI (2009) Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter. Br J Pharmacol 156:1178-1184.
27. Newman AH, Kline RH, Allen AC, Izenwasser S, George C, and Katz JL (1995) Novel 4′ substituted and 4′,4″ disubstituted 3α-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors. J Med Chem 38:3933-3940.
28. Othman AA, Newman AH, and Eddington ND (2008) The novel N-substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse. J Pharm Sci 97:5453-5470.
29. Raje S, Cao J, Newman AH, Gao H, and Eddington ND (2003) Evaluation of the blood-brain barrier transport, population pharmacokinetics, and brain distribution of benztropine analogs and cocaine using in vitro and in vivo techniques. J Pharmacol Exp Ther 307:801-808.
30. Robarge MJ, Agoston GE, Izenwasser S, Kopajtic T, George C, Katz JL, and Newman AH (2000) Highly selective chiral N-substituted 3α-[bis(4′- fluorophenyl)methoxyl] tropane analogues for the dopamine transporter: synthesis and comparative molecular field analysis. J Med Chem 43:1085-1093.
31. Syed SA, Newman AH, Othman AA, and Eddington ND (2008) Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse. J Pharm Sci 97:1993-2007.
32. Tanda G, Ebbs A, Newman AH, and Katz JL (2005) Effects of 4′-chloro-3α-(diphenylmethoxy)-tropane on mesostriatal, mesocortical, and mesolimbic dopamine transmission: comparison with effects of cocaine. J Pharmacol Exp Ther 313:613-620.
33. Tanda G, Newman AH, Ebbs AL, Tronci V, Green JL, Tallarida RJ, and Katz JL (2009) Combinations of cocaine with other dopamine uptake inhibitors: assessment of additivity. J Pharmacol Exp Ther 330:802-809.
34. Tanda G, Newman AH, and Katz JL (2009) Discovery of drugs to treat cocaine dependence: behavioral and neurochemical effects of atypical dopamine transport inhibitors. Adv Pharmacol 57:253-289.
35. Velázquez-Sánchez C, Ferragud A, Hernández-Rabaza V, Nácher A, Merino V, Cardá M, Murga J, and Canales JJ (2009) The dopamine uptake inhibitor 3α-[bis(4′-fluorophenyl)metoxy]-tropane reduces cocaine-induced early-gene expression, locomotor activity, and conditioned reward. Neuropsychopharmacology 34:2497-2507.
36. Velázquez-Sánchez C, Ferragud A, Murga J, Cardá M, and Canales JJ (2010) The high affinity dopamine uptake inhibitor, JHW 007, blocks cocaine-induced reward, locomotor stimulation and sensitization. Eur Neuropsychopharmacol 20:501-508.
37. Woolverton WL, Rowlett JK, Wilcox KM, Paul IA, Kline RH, Newman AH, and Katz JL (2000) 3′- and 4′-Chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys. Psychopharmacology 147:426-435.
38. Yamashita A, Singh SK, Kawate T, Jin Y, and Gouaux E (2005) Crystal structure of a bacterial homologue of Na+/Cl-dependent neurotransmitter transporters. Nature 437:215-223. (Pubitemid 41294479)