The novel N-substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse

Journal of Pharmaceutical Sciences

Volumn 97, Issue 12, 2008, Pages 5453-5470

  Othman, Ahmed A ^a,b,d   Newman, Amy H ^c   Eddington, Natalie D ^a  

^a UNIVERSITY OF MARYLAND SCHOOL OF PHARMACY   (United States)

^b CAIRO UNIVERSITY   (Egypt)

^c NATIONAL INSTITUTE ON DRUG ABUSE   (United States)

^d ABBOTT LABORATORIES   (United States)

Author keywords

Cocaine abuse; Microdialysis; Pharmacodynamics; Pharmacokinetics; Substitution therapy

Indexed keywords

BENZATROPINE; CYTOCHROME P450 2C11; CYTOCHROME P450 2C19; CYTOCHROME P450 2D1; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; DOPAMINE TRANSPORTER; GA 2 50; GLYCOPROTEIN P; N (DIMETHYL) 3A [(BIS 4' FLUOROPHENYL)METHOXY]TROPANE; N [(2'' AMINO 3'' METHYL N BUTYL) 3ALPHA [(BIS 4' FLUOROPHENYL)METHOXY]TROPANE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL MEMBRANE PERMEABILITY; COCAINE DEPENDENCE; CONTROLLED STUDY; DOPAMINE UPTAKE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG SELECTIVITY; HUMAN; HUMAN CELL; IN VITRO STUDY; MALE; MICRODIALYSIS; NONHUMAN; NUCLEUS ACCUMBENS; RAT;

EID: 57349154337     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.21389     Document Type: Article

References (46)

1. SAMHSA (Substance Abuse and Mental Health Services Administration). 2006. Results from the 2005 National Survey on Drug Use and Health: National Findings. ed., Rockville, MD: Department of Health and Human Services (Office of Applied Studies, NSDUH Series H-30, DHHS Publication No. SMA 06-4194).
2. Sofuoglu M, Kosten TR. 2005. Novel approaches to the treatment of cocaine addiction. CNS Drugs 19:13-25.
3. Grabowski J, Shearer J, Merrill J, Negus SS. 2004. Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav 29:1439-1464.
4. Jarvik M, Henningfield J. 1993. Pharmacological adjuncts for the treatment of tobaco dependence. In: Orleans C, Slade J, editors. Nicotine addiction:principles and management. New York: Oxford University Press. pp 245-261.
5. Ward J, Mattick R, Hall W. 1998. Methadone maintainance treatment and other opioid replacement therapies. editors. Amsterdam: Howard Academic Publishers.
6. Negus SS, Mello NK. 2003. Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys. Psychopharmacology (Berl) 167:324-332.
7. Grabowski J, Rhoades H, Schmitz J, Stotts A, Daruzska LA, Creson D, Moeller FG. 2001. Dextroamphetamine for cocaine-dependence treatment: A double-blind randomized clinical trial. J Clin Psychopharmacol 21:522-526.
8. Grabowski J, Rhoades H, Stotts A, Cowan K, Kopecky C, Dougherty A, Moeller FG, Hassan S, Schmitz J. 2004. Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: Two double-blind randomized clinical trials. Neuropsychopharmacology 29:969-981.
9. Koe BK. 1976. Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain. J Pharmacol Exp Ther 199:649-661.
10. Madras BK, Fahey MA, Bergman J, Canfield DR, Spealman RD. 1989. Effects of cocaine and related drugs in nonhuman primates. I. [3H]cocaine binding sites in caudate-putamen. J Pharmacol Exp Ther 251:131-141.
11. Kuhar MJ, Ritz MC, Boja JW. 1991. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 14:299-302.
12. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. 1987. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219-1223.
13. Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N, Hitzemann R, Shea CE. 1997. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827-830.
14. Carroll FI, Howell LL, Kuhar MJ. 1999. Pharmacotherapies for treatment of cocaine abuse: Preclinical aspects. J Med Chem 42:2721-2736.
15. Quinn DI, Wodak A, Day RO. 1997. Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users. Clin Pharmacokinet 33:344-400.
16. Gorelick DA. 1998. The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. Adv Pharmacol 42:995-997.
17. Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, Dewey S, Ashby C, Liebermann J, Hitzemann R, et al. 1995. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 52:456-463.
18. Volkow ND. 2006. Stimulant medications: How to minimize their reinforcing effects? Am J Psychiatry 163:359-361.
19. Newman AH, Katz JL. 2008. The Benztropines: Atypical dopamine uptake inhibitors that provide clues about cocaine's mechanism at the dopamine transporter. In: Trudell M, Izenwasser S, editors. Dopamine transporters: Chemistry, biology and pharmacology (in press).
20. Rothman RB, Baumann MH, Prisinzano TE, Newman AH. 2008. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol 75:2-16.
21. Katz JL, Kopajtic TA, Agoston GE, 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.
22. Woolverton WL, Hecht GS, Agoston GE, Katz JL, Newman AH. 2001. Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys. Psychopharmacology (Berl) 154:375-382.
23. Desai RI, Kopajtic TA, Koffarnus M, Newman AH, Katz JL. 2005. Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine. J Neurosci 25:1889-1893.
24. Raje S, Cao J, Newman AH, Gao H, 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.
25. Raje S, Cornish J, Newman AH, Cao J, Katz JL, Eddington ND. 2005. Pharmacodynamic assessment of the benztropine analogues AHN-1055 and AHN-2005 using intracerebral microdialysis to evaluate brain dopamine levels and pharmacokinetic/pharmacodynamic modeling. Pharm Res 22:603-612.
26. Othman AA, Syed SA, Newman AH, Eddington ND. 2007. Transport, metabolism, and in vivo population pharmacokinetics of the chloro benztropine analogs, a class of compounds extensively evaluated in animal models of drug abuse. J Pharmacol Exp Ther 320:344-353.
27. Othman AA, Newman AH, Eddington ND. 2007. Applicability of the dopamine and rate hypotheses in explaining the differences in behavioral pharmacology of the chloro-benztropine analogs: Studies conducted using intracerebral microdialysis and population pharmacodynamic modeling. J Pharmacol Exp Ther 322:760-769.
28. Robarge MJ, Agoston GE, Izenwasser S, Kopajtic T, George C, Katz JL, Newman AH. 2000. 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 43:1085-1093.
29. O'Callaghan MJ, Newman AH, Kopajtic T, Katz JL. 2003. The discriminative stimulus effects of N-substituted benztropine analogs on cocaine discrimination in rats. Presented to the 65th annual scientific meeting of the college on problems of drug dependence.
30. Agoston GE, Wu JH, Izenwasser S, George C, Katz J, Kline RH, Newman AH. 1997. Novel N-substituted 3 alpha-[bis(4′-fluorophenyl)methoxy]tropane analogues: Selective ligands for the dopamine transporter. J Med Chem 40:4329-4339.
31. Baumann MH, Clark RD, Budzynski AG, Partilla JS, Blough BE, Rothman RB. 2005. N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy'). Neuropsychopharmacology 30:550-560.
32. Paxinos G, Watson C. 1986. The rat brain in stereotaxic coordinates, 3rd ed. New York: Academic Press.
33. Baumann MH, Rutter JJ. 2003. Application of in vivo microdialysis methods to the study of psychomotor stimulant drugs. In: Waterhouse BD, editor. Methods in drug abuse research: Cellular and circuit level analyses, 1st ed. Boca Raton, Fl: CRC Press. pp 51-86.
34. Raje S, Dowling TC, Eddington ND. 2002. Determination of the benztropine analog AHN-1055, a dopamine uptake inhibitor, in rat plasma and brain by high-performance liquid chromatography with ultraviolet absorbance detection. J Chromatogr B Anal Technol Biomed Life Sci 768:305-313.
35. Naritomi Y, Terashita S, Kagayama A, Sugiyama Y. 2003. Utility of hepatocytes in predicting drug metabolism: Comparison of hepatic intrinsic clearance in rats and humans in vivo and in vitro. Drug Metab Dispos 31:580-588.
36. Hing JP, Woolfrey SG, Greenslade D, Wright PM. 2001. Is mixed effects modeling or naive pooled data analysis preferred for the interpretation of single sample per subject toxicokinetic data? J Pharmacokinet Pharmacodyn 28:193-210.
37. Rothman RB. 1990. High affinity dopamine reuptake inhibitors as potential cocaine antagonists: A strategy for drug development. Life Sci 46:PL17-PL21.
38. He H, McKay G, Midha KK. 1995. Phase I and II metabolites of benztropine in rat urine and bile. Xenobiotica 25:857-872.
39. Syed SA, Newman AH, Othman AA, Eddington ND. 2008. Population pharmacokinetics, brain distribution, and pharmacodynamics of 2(nd) generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse. J Pharm Sci Published online September 19, 2007.
40. Kuhar MJ, Pilotte NS. 1996. Neurochemical changes in cocaine withdrawal. Trends Pharmacol Sci 17:260-264.
41. Baumann MH, Char GU, De Costa BR, Rice KC, Rothman RB. 1994. GBR12909 attenuates cocaine-induced activation of mesolimbic dopamine neurons in the rat. J Pharmacol Exp Ther 271:1216-1222.
42. Volkow ND, Swanson JM. 2003. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADH. Am J Psychiatry 160:1909-1918.
43. Ranaldi R, Woolverton WL. 2002. Self-administration of cocaine: Scopolamine combinations by rhesus monkeys. Psychopharmacology (Berl) 161:442-448.
44. De Klippel N, Sarre S, Ebinger G, Michotte Y. 1993. Effect of M1- and M2-muscarinic drugs on striatal dopamine release and metabolism: An in vivo microdialysis study comparing normal and 6-hydroxydopamine-lesioned rats. Brain Res 630:57-64.
45. Tanda G, Ebbs AL, Kopajtic TA, Elias LM, Campbell BL, Newman AH, Katz JL. 2007. Effects of muscarinic M1 receptor blockade on cocaine-induced elevations of brain dopamine levels and locomotor behavior in rats. J Pharmacol Exp Ther 321:334-344.
46. Desai RI, Kopajtic TA, French D, Newman AH, Katz JL. 2005. 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.