Dopamine transporter as target for drug development of cocaine dependence medications.

Because much evidence implicates the dopamine transporter in the reinforcing effects of cocaine, development of potential medications for cocaine dependence has included the dopamine transporter as a target. The present overview covers progress in the drug development area regarding several classes of dopamine uptake inhibitors, with an emphasis on structure-activity relationships that enhance potency and selectivity at transporters for dopamine compared with those for serotonin or norepinephrine. The following categories of compounds are covered: tropane, benztropine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR), methylphenidate, mazindol, and phencyclidine analogs. Activity at transporters as well as on behavior is highlighted.

[1]  Z. Chen,et al.  Synthesis of 6- and 7- hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. , 2001, Journal of Medicinal Chemistry.

[2]  R. Meier,et al.  Ritalin, eine neuartige synthetische Verbindung mit spezifischer zentralerregender Wirkungskomponente , 1954, Klinische Wochenschrift.

[3]  Kenneth M. Johnson,et al.  Chemistry and biology of the 2β-alkyl-3β-phenyl analogues of cocaine : subnanomolar affinity ligands that suggest a new pharmacophore model at the C-2 position , 1995 .

[4]  M. Nader,et al.  The reinforcing and discriminative stimulus effects of the novel cocaine analog 2β-propanoyl-3β-(4-tolyl)-tropane in rhesus monkeys , 1997 .

[5]  McCance Ef.  Overview of potential treatment medications for cocaine dependence. , 1997 .

[6]  M. Reith,et al.  Structure-activity relationship studies of novel 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: synthesis and biological evaluation at the dopamine and serotonin transporter sites. , 1996, Journal of medicinal chemistry.

[7]  M. Kuhar,et al.  Studies of selected phenyltropanes at monoamine transporters. , 1999, Drug and alcohol dependence.

[8]  N. Greig,et al.  GBR12909 antagonizes the ability of cocaine to elevate extracellular levels of dopamine , 1991, Pharmacology Biochemistry and Behavior.

[9]  H. Deutsch,et al.  Biochemical and behavioral characterization of novel methylphenidate analogs. , 2002, The Journal of pharmacology and experimental therapeutics.

[10]  H. Kung,et al.  A Stereoselective Synthesis of dl-threo-Methylphenidate: Preparation and Biological Evaluation of Novel Analogues† , 1998 .

[11]  A. Newman,et al.  Structure-activity relationships at monoamine transporters and muscarinic receptors for N-substituted-3alpha-(3'-chloro-, 4'-chloro-, and 4',4''-dichloro-substituted-diphenyl)methoxytropanes. , 2001, Journal of medicinal chemistry.

[12]  A. Lajtha,et al.  Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior. , 1986, Biochemical pharmacology.

[13]  R. Mark Wightman,et al.  Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter , 1996, Nature.

[14]  J S Fowler,et al.  Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. , 1995, Archives of general psychiatry.

[15]  A. Horn.  Dopamine uptake: A review of progress in the last decade , 1990, Progress in Neurobiology.

[16]  Kenneth M. Johnson,et al.  Differential binding and dopamine uptake activity of cocaine analogues modified at nitrogen , 1994 .

[17]  Design, synthesis, and activity of novel cis- and trans-3,6-disubstituted pyran biomimetics of 3,6-disubstituted piperidine as potential ligands for the dopamine transporter. , 2003, Bioorganic & medicinal chemistry letters.

[18]  B. Madras,et al.  Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate. , 2003, Journal of medicinal chemistry.

[19]  P. H. Andersen.  The dopamine uptake inhibitor GBR 12909: selectivity and molecular mechanism of action , 1989 .

[20]  B. Madras,et al.  The Discovery of an Unusually Selective and Novel Cocaine Analogue: Difluoropine. Synthesis and Inhibition of Binding at Cocaine Recognition Sites. , 1994 .

[21]  N. Volkow,et al.  Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain. , 1999, Life sciences.

[22]  R. Spealman,et al.  Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys. , 1989, The Journal of pharmacology and experimental therapeutics.

[23]  A. Fischman,et al.  Design, synthesis, and biological evaluation of novel non-piperazine analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines as dopamine transporter inhibitors. , 1999, Journal of medicinal chemistry.

[24]  A. Kozikowski,et al.  Structure-activity relationship studies of N-sulfonyl analogs of cocaine: role of ionic interaction in cocaine binding. , 1994, Journal of medicinal chemistry.

[25]  F. Colpaert,et al.  The phencyclidine (PCP) analog N-[1-(2-benzo(B)thiophenyl) cyclohexyl]piperidine shares cocaine-like but not other characteristic behavioral effects with PCP, ketamine and MK-801. , 1989, The Journal of pharmacology and experimental therapeutics.

[26]  M. Reith,et al.  Structure−Activity Relationship Studies of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidine Derivatives and Their N-Analogues: Evaluation of Behavioral Activity of O- and N-Analogues and Their Binding to Monoamine Transporters , 2001 .

[27]  T. Kopajtic,et al.  Synthesis and biological evaluation of 2-substituted 3beta-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters. , 2002, Journal of medicinal chemistry.

[28]  G. Di Chiara,et al.  Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[29]  G. Di Chiara,et al.  Cocaine and Amphetamine Increase Extracellular Dopamine in the Nucleus Accumbens of Mice Lacking the Dopamine Transporter Gene , 2001, The Journal of Neuroscience.

[30]  J. Vignon,et al.  Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs , 1989, Pharmacology Biochemistry and Behavior.

[31]  M. J. Kuhar,et al.  The dopamine hypothesis of the reinforcing properties of cocaine , 1991, Trends in Neurosciences.

[32]  M. Reith,et al.  Highly selective, novel analogs of 4-[2-(diphenylmethoxy)ethyl]- 1-benzylpiperidine for the dopamine transporter: effect of different aromatic substitutions on their affinity and selectivity. , 1997, Journal of medicinal chemistry.

[33]  E. Gruszecka-Kowalik,et al.  Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs. , 1996, Journal of medicinal chemistry.

[34]  R. H. Kline,et al.  Synthesis of 3-carbamoylecgonine methyl ester analogues as inhibitors of cocaine binding and dopamine uptake. , 1991, Journal of medicinal chemistry.

[35]  M. Kuhar,et al.  2 beta-substituted analogues of cocaine. Synthesis and inhibition of binding to the cocaine receptor. , 1992, Journal of medicinal chemistry.

[36]  E. Domino,et al.  Sigma and Phencyclidine: Like Compounds As Molecular Probes in Biology , 1988 .

[37]  S. J. Gatley,et al.  Relationship between subjective effects of cocaine and dopamine transporter occupancy , 1997, Nature.

[38]  K. Rice,et al.  Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: chiral hydroxyl-containing derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine. , 2002, Journal of medicinal chemistry.

[39]  Ruoyan Chen,et al.  Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. , 1996, Life sciences.

[40]  F I Carroll,et al.  Synthesis, ligand binding, and QSAR (CoMFA and classical) study of 3 beta-(3'-substituted phenyl)-, 3 beta-(4'-substituted phenyl)-, and 3 beta-(3',4'-disubstituted phenyl)tropane-2 beta-carboxylic acid methyl esters. , 1994, Journal of medicinal chemistry.

[41]  S Kitayama,et al.  Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A. Kozikowski,et al.  Methoxylation of cocaine reduces binding affinity and produces compounds of differential binding and dopamine uptake inhibitory activity: discovery of a weak cocaine "antagonist". , 1993, Journal of medicinal chemistry.

[43]  K. Neve,et al.  Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. , 1999, The Journal of pharmacology and experimental therapeutics.

[44]  M. Kuhar,et al.  Synthesis, Ligand Binding, and Quantitative Structure−Activity Relationship Study of 3β-(4‘-Substituted phenyl)-2β-heterocyclic Tropanes: Evidence for an Electrostatic Interaction at the 2β-Position , 1996 .

[45]  R. L. Clarke,et al.  Compounds affecting the central nervous system. 4. 3 Beta-phenyltropane-2-carboxylic esters and analogs. , 1973, Journal of medicinal chemistry.

[46]  F I Carroll,et al.  Synthesis and ligand binding of cocaine isomers at the cocaine receptor. , 1991, Journal of medicinal chemistry.

[47]  G. Breese,et al.  Pharmacology of the enantiomers of threo-methylphenidate. , 1987, The Journal of pharmacology and experimental therapeutics.

[48]  H. Deutsch,et al.  Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction. , 2001, European journal of medicinal chemistry.

[49]  R. H. Kline,et al.  3‘-Chloro-3α-(diphenylmethoxy)tropane But Not 4‘-Chloro-3α- (diphenylmethoxy)tropane Produces a Cocaine-like Behavioral Profile† , 1997 .

[50]  J. Neumeyer,et al.  Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor. , 1991, Journal of medicinal chemistry.

[51]  M. Kuhar,et al.  Pharmacotherapies for treatment of cocaine abuse: preclinical aspects. , 1999, Journal of medicinal chemistry.

[52]  R. Gainetdinov,et al.  Cocaine self-administration in dopamine-transporter knockout mice , 1998, Nature Neuroscience.

[53]  F I Carroll,et al.  Synthesis, ligand binding, QSAR, and CoMFA study of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters. , 1991, Journal of medicinal chemistry.

[54]  M. Kuhar,et al.  Halogenated mazindol analogs as potential inhibitors of the cocaine binding site at the dopamine transporter. , 1996, Journal of medicinal chemistry.

[55]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[56]  S. Childers,et al.  Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site. , 1996, Journal of medicinal chemistry.

[57]  B. Madras,et al.  The discovery of an unusually selective and novel cocaine analog: difluoropine. Synthesis and inhibition of binding at cocaine recognition sites. , 1994, Journal of medicinal chemistry.

[58]  K. Rice,et al.  Sustained decrease in cocaine-maintained responding in rhesus monkeys with 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate, a long-acting ester derivative of GBR 12909. , 1996, Journal of medicinal chemistry.

[59]  M. Kuhar,et al.  Cocaine receptors on dopamine transporters are related to self-administration of cocaine. , 1987, Science.

[60]  Kenneth M. Johnson,et al.  TUNING THE SELECTIVITY OF MONOAMINE TRANSPORTER INHIBITORS BY THE STEREOCHEMISTRY OF THE NITROGEN LONE PAIR , 1998 .

[61]  R. H. Kline,et al.  Novel 3alpha-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine. , 1999, The Journal of pharmacology and experimental therapeutics.

[62]  A. Janowsky,et al.  Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter. , 2002, Journal of medicinal chemistry.

[63]  J. B. Pitner,et al.  N-modified analogues of cocaine: synthesis and inhibition of binding to the cocaine receptor. , 1992, Journal of medicinal chemistry.

[64]  Smith,et al.  Dopaminergic agents for the treatment of cocaine abuse. , 1999, Drug discovery today.

[65]  B. Yamamoto,et al.  Regulation of Extracellular Dopamine by the Norepinephrine Transporter , 1998, Journal of neurochemistry.

[66]  M. Reith,et al.  Potent and selective ligands for the dopamine transporter (DAT): structure-activity relationship studies of novel 4-[2-(diphenylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine analogues. , 1998, Journal of medicinal chemistry.

[67]  M. Kuhar,et al.  Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study. , 1990, Life sciences.

[68]  M. Nader,et al.  Further evaluation of the reinforcing effects of the novel cocaine analog 2β-propanoyl-3β-(4-tolyl)-tropane (PTT) in rhesus monkeys , 1998, Psychopharmacology.

[69]  S. Mascarella,et al.  Dopamine transporter uptake blockers: Structure-activity relationships , 1995 .

[70]  Y. Claustre,et al.  Anorectic activities of serotonin uptake inhibitors: correlation with their potencies at inhibiting serotonin uptake in vivo and 3H-mazindol binding in vitro. , 1988, Life sciences.

[71]  S. Snyder,et al.  [3H]mazindol binding associated with neuronal dopamine and norepinephrine uptake sites. , 1984, Molecular pharmacology.

[72]  F. Bloom,et al.  Cellular and molecular mechanisms of drug dependence. , 1988, Science.

[73]  D. Collard,et al.  Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors. , 1999, Journal of medicinal chemistry.

[74]  P. H. Andersen.  Biochemical and Pharmacological Characterization of [3H]GBR 12935 Binding In Vitro to Rat Striatal Membranes: Labeling of the Dopamine Uptake Complex , 1987, Journal of neurochemistry.

[75]  R. Spealman,et al.  Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development , 2002, Psychopharmacology.

[76]  P. V. D. Zee,et al.  ARYL 1,4-DIALK(EN)YLPIPERAZINES AS SELECTIVE AND VERY POTENT INHIBITORS OF DOPAMINE UPTAKE , 1981 .

[77]  L. Howell,et al.  The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates. , 2001, The Journal of pharmacology and experimental therapeutics.

[78]  D. Gorelick.  The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. , 1998, Advances in pharmacology.

[79]  C. George,et al.  Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton. , 1998, Journal of medicinal chemistry.

[80]  K. Rice,et al.  Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors. , 1997, Journal of medicinal chemistry.

[81]  A. Andrews,et al.  Differential Reinforcing Effects of Cocaine and GBR-12909: Biochemical Evidence for Divergent Neuroadaptive Changes in the Mesolimbic Dopaminergic System , 1996, The Journal of Neuroscience.

[82]  J. Glowa,et al.  Dose-response analysis in risk assessment: evaluation of behavioral specificity. , 1996, Environmental health perspectives.

[83]  M. Kuhar,et al.  Comparative behavioral pharmacology of cocaine and the selective dopamine uptake inhibitor RTI-113 in the squirrel monkey. , 2000, The Journal of pharmacology and experimental therapeutics.

[84]  C. George,et al.  Further evidence for a dopamine reuptake pharmacophore. The effect of N-methylation on Threo-methylphenidate and its analogs , 1997 .

[85]  J. Witkin,et al.  Behavioral effects of selective dopaminergic compounds in rats discriminating cocaine injections. , 1991, The Journal of pharmacology and experimental therapeutics.

[86]  K. Rice,et al.  Development of novel, potent, and selective dopamine reuptake inhibitors through alteration of the piperazine ring of 1-[2-(diphenylmethoxy)ethyl]-and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909). , 1996, Journal of medicinal chemistry.

[87]  C. George,et al.  High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: stereospecific interactions in vitro and in vivo. , 2003, Journal of medicinal chemistry.

[88]  Z. Chen,et al.  2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters. , 1997, Journal of medicinal chemistry.

[89]  J. Costentin,et al.  Thermodynamics of the binding of BTCP (GK 13) and related derivatives on the dopamine neuronal carrier. , 1994, European journal of pharmacology.

[90]  T. Seale,et al.  Synthesis and ligand binding studies of 4'-iodobenzoyl esters of tropanes and piperidines at the dopamine transporter. , 1997, Journal of medicinal chemistry.

[91]  M. Reith,et al.  O-526, a piperidine analog of GBR 12909, retains high affinity for the dopamine transporter in monkey caudate-putamen. , 1994, European journal of pharmacology.

[92]  S. Singh,et al.  Chemistry, design, and structure-activity relationship of cocaine antagonists. , 2000, Chemical reviews.

[93]  M. Kuhar,et al.  Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs. , 1996, Journal of medicinal chemistry.

[94]  R. Spealman,et al.  Effects of cocaine and related drugs in nonhuman primates. II. Stimulant effects on schedule-controlled behavior. , 1989, The Journal of pharmacology and experimental therapeutics.

[95]  E. Uhlenhuth,et al.  Reinforcing and subjective effects of several anorectics in normal human volunteers. , 1987, The Journal of pharmacology and experimental therapeutics.

[96]  M. Reith,et al.  Rational design and synthesis of novel 2,5-disubstituted cis- and trans-piperidine derivatives exhibiting differential activity for the dopamine transporter. , 2001, Bioorganic & medicinal chemistry letters.

[97]  N. Mello,et al.  Preclinical Evaluation of Pharmacotherapies for Treatment of Cocaine and Opioid Abuse Using Drug Self-Administration Procedures , 1996, Neuropsychopharmacology.

[98]  R. H. Kline,et al.  Novel 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors. , 1995, Journal of medicinal chemistry.

[99]  B. de Costa,et al.  Synthesis and biological evaluation of 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine homologues at dopamine-uptake and phencyclidine- and sigma-binding sites. , 1993, Journal of Medicinal Chemistry.

[100]  K. Rice,et al.  Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: I. Dependence on unit dose of cocaine. , 1995 .