Novel 3.alpha.-(Diphenylmethoxy)tropane Analogs: Potent Dopamine Uptake Inhibitors without Cocaine-like Behavioral Profiles

Newman, Amy Hauck; Allen, Andrew C.; Izenwasser, Sari; Katz, Jonathan L.

doi:10.1021/jm00041a002

Cited by 112 publications

(158 citation statements)

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“…(cocaine) in a volume of 1.0 ml/kg. In the binding assays (Table 1), we also tested the following BZT analogs (Newman et al, 1994): AHN 1-055, 4Ј-4Љ-diCl-BZT, and 4-Cl-BZT. The hypothesis of the study was that antagonism at M 1 muscarinic receptors would reduce the neurochemical effects of cocaine; however, initial studies with 0.3 mg/kg TZP showed an increase in neurochemical effects.…”

Section: Methodsmentioning

confidence: 99%

“…Among the many molecules that have been synthesized in research on medications for cocaine abuse, analogs of benztropine (BZT) are of interest because they have a high affinity for the DA transporter (Newman et al, 1994;Newman and Kulkarni, 2002), while showing reduced cocaine-like activities in experimental animals (Katz et al, 1999(Katz et al, , 2001, including reduced reinforcing effects (Woolverton et al, 2000). Like the parent compound, many of the BZT analogs have affinity for acetylcholine muscarinic receptors.…”

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confidence: 99%

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Effects of Muscarinic M₁Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

Ebbs¹,

Kopajtic²,

Elias³

et al. 2007

J Pharmacol Exp Ther

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Cholinergic muscarinic systems have been shown to influence dopaminergic function in the central nervous system. In addition, previous studies of benztropine analogs that inhibit dopamine uptake and show antagonism at muscarinic receptors show these drugs to be less effective than cocaine in producing its various prototypic effects such as locomotor stimulation. Because previous pharmacological studies on these topics have used nonselective M 1 antagonists, we examined the interactions of preferential M 1 muscarinic antagonists and cocaine. Dose-dependent increases in extracellular levels of dopamine in selected brain areas, the nucleus accumbens (NAc) shell and core, and the prefrontal cortex, were produced by cocaine but not by the preferential M 1 antagonists telenzepine and trihexyphenidyl. When administered with cocaine, however, both M 1 antagonists dose-dependently increased the effects of cocaine on dopamine in the NAc shell, and these effects were selective in that they were not obtained in the NAc core or in the prefrontal cortex. Telenzepine also increased locomotor activity, although the effect was small compared with that of cocaine. The locomotor stimulant effects of trihexyphenidyl, in contrast, approached those of cocaine. Telenzepine attenuated, whereas trihexyphenidyl enhanced the locomotor stimulant effects of cocaine, with neither drug facilitating cocaine-induced stereotypy. The present results indicate that preferential antagonist effects at muscarinic M 1 receptors do not uniformly alter all of the effects of cocaine, nor do they explain the differences in effects of cocaine and benztropine analogs, and that the alterations in dopamine levels in the NAc shell do not predict the behavioral effects of the interactions with cocaine.Both clinical and preclinical data support the existence of extensive interactions between the dopaminergic and cholinergic muscarinic systems in various central nervous system functions and disease, including Parkinson's disease, schizophrenia, and cocaine dependence. Preclinical studies have shown that the administration of muscarinic M 1 receptor agonists and antagonists increase or decrease, respectively, levels of extracellular DA in striatal and cortical areas (Xu et al., 1989;De Klippel et al., 1993;Gronier et al., 2000). Cocaine self-administration by rats increases concentrations of acetylcholine in the NAc shell (Mark et al., 1999) and increases acetylcholine turnover rates in several brain regions (Smith et al., 2004a,b) compared with passively administered cocaine. Changes in acetylcholine resulting from cocaine administration seem to be due to activation of cholinergic interneurons in the NAc and dorsal striatum (Berlanga et al., 2003), and cocaine treatment can produce an up-regulation of muscarinic binding at 1 day, but not 30 min after treatment (Macêdo et al., 2001). Finally, cholinergic lesions of posterior nucleus accumbens and ventral pallidal regions produced a leftward shift of the cocaine dose-effect curve in rats trained to self-adm...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Effects of Muscarinic M₁Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

Ebbs¹,

Kopajtic²,

Elias³

et al. 2007

J Pharmacol Exp Ther

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“…The mesocorticolimbic dopamine (DA) system plays a crucial role (3 -5), but several lines of evidence have clearly demonstrated that DA is not the sole mediator of the behavioral effects of psychostimulant drugs. The occupation of the DA transporter by selective DA reuptake blockers does not correlate with their locomotor stimulant effects (6,7). In addition, the expression of psychostimulant-induced locomotor sensitization can be dissociated from the expression of the sensitization of the DA response in the nucleus accumbens (8,9), striatum (10,11) and prefrontal cortex (12).…”

Section: Introductionmentioning

confidence: 99%

Neuropsychotoxicity of Abused Drugs: Effects of Serotonin Receptor Ligands on Methamphetamine- and Cocaine-Induced Behavioral Sensitization in Mice

et al. 2008

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Abstract. Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play key roles as the neural substrates mediating behavioral sensitization, but the role of the serotonin (5-HT) system in the sensitization is not fully elucidated. We have recently demonstrated that osemozotan, a specific 5-HT 1A -receptor agonist, and ritanserin, a 5-HT 2 -receptor antagonist, inhibited the expression and development of both methamphetamine-and cocaine-induced behavioral sensitization in mice and that these drugs attenuated the maintenance of behavioral sensitization of methamphetamine, but not that of cocaine. We also found that azasetron, a 5-HT 3 -receptor antagonist, inhibited the expression and development of the sensitization induced by methamphetamine and cocaine, respectively. Neurochemical studies using a microdialysis technique showed that repeated methamphetamine enhanced the methamphetamine-induced increase in 5-HT release in the prefrontal cortex. The sensitization of 5-HT release in methamphetamine-treated mice was attenuated by osemozotan and ritanserin. These findings suggest that the 5-HT system plays an important role in methamphetamine-and cocaine-induced behavioral sensitization in mice and imply that 5-HT 1A -receptor agonists and 5-HT 2 -receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.

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“…The development of drugs, including cocaine and benztropine analogs, that inhibit the DAT and yet do not display behavioral profiles similar to cocaine in animal models (Newman et al, 1994;Newman and Kulkarni, 2002;Woolverton et al, 2002;Kozikowski et al, 2003;Desai et al, 2005) suggest that such a medication is attainable. By combining medicinal chemistry efforts with DAT structure-function molecular pharmacology, computeraided rational design of agents that counter the actions of abused psychostimulants should be feasible.…”

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Recognition of Benztropine by the Dopamine Transporter (DAT) Differs from That of the Classical Dopamine Uptake Inhibitors Cocaine, Methylphenidate, and Mazindol as a Function of a DAT Transmembrane 1 Aspartic Acid Residue

Ukairo

Bondi

Newman

et al. 2005

J Pharmacol Exp Ther

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Binding of cocaine to the dopamine transporter (DAT) protein blocks synaptic dopamine clearance, triggering the psychoactive effects associated with the drug; the discrete drug-protein interactions, however, remain poorly understood. A longstanding postulate holds that cocaine inhibits DAT-mediated dopamine transport via competition with dopamine for formation of an ionic bond with the DAT transmembrane aspartic acid residue D79. In the present study, DAT mutations of this residue were generated and assayed for translocation of radiolabeled dopamine and binding of radiolabeled DAT inhibitors under identical conditions. When feasible, dopamine uptake inhibition potency and apparent binding affinity K i values were determined for structurally diverse DAT inhibitors. The glutamic acid substitution mutant (D79E) displayed values indistinguishable from wild-type DAT in both assays for the charge-neutral cocaine analog 8-oxa-norcocaine, a finding not supportive of the D79 "salt bridge" ligand-docking model. In addressing whether the D79 side chain contributes to the DAT binding sites of other portions of the cocaine pharmacophore, only inhibitors with modifications of the tropane ring C-3 substituent, i.e., benztropine and its analogs, displayed a substantially altered dopamine uptake inhibition potency as a function of the D79E mutation. A single conservative amino acid substitution thus differentiated structural requirements for benztropine function relative to those for all other classical DAT inhibitors. Distinguishing the precise mechanism of action of this DAT inhibitor with relatively low abuse liability from that of cocaine may be attainable using DAT mutagenesis and other structure-function studies, opening the door to rational design of therapeutic agents for cocaine abuse.Millions of individuals worldwide are addicted to cocaine, a public health crisis that also carries a substantial burden to society in the form of medical expenses, lost earnings, and increased crime associated with psychostimulant abuse. Although therapeutics including buprenorphine and methadone are clinically accessible to treat opiate abuse and addiction, no such Food and Drug Administration-approved medication is available for the treatment of cocaine addiction. Pharmacological and behavioral studies have established that the euphoric and addictive effects of cocaine are initiated by its binding to the dopamine transporter (DAT) protein, blocking clearance of dopamine from central nervous system synapses and thereby prolonging dopaminergic neurotransmission in brain areas associated with reward (Ritz et al., 1987). The DAT is therefore a logical target for development of medications for cocaine abuse. Elucidating the relationship between the DAT and its substrates and inhibitors is essential, especially regarding cocaine points of contact with the DAT protein relevant to its inhibition of dopamine uptake.Because dopamine and all classical DAT inhibitors possess a protonated nitrogen atom, a longstanding model for cocaine

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Novel 3.alpha.-(Diphenylmethoxy)tropane Analogs: Potent Dopamine Uptake Inhibitors without Cocaine-like Behavioral Profiles

Cited by 112 publications

References 12 publications

Effects of Muscarinic M₁Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

Effects of Muscarinic M₁Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

Neuropsychotoxicity of Abused Drugs: Effects of Serotonin Receptor Ligands on Methamphetamine- and Cocaine-Induced Behavioral Sensitization in Mice

Recognition of Benztropine by the Dopamine Transporter (DAT) Differs from That of the Classical Dopamine Uptake Inhibitors Cocaine, Methylphenidate, and Mazindol as a Function of a DAT Transmembrane 1 Aspartic Acid Residue

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Novel 3.alpha.-(Diphenylmethoxy)tropane Analogs: Potent Dopamine Uptake Inhibitors without Cocaine-like Behavioral Profiles

Cited by 112 publications

References 12 publications

Effects of Muscarinic M1Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

Effects of Muscarinic M1Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

Neuropsychotoxicity of Abused Drugs: Effects of Serotonin Receptor Ligands on Methamphetamine- and Cocaine-Induced Behavioral Sensitization in Mice

Recognition of Benztropine by the Dopamine Transporter (DAT) Differs from That of the Classical Dopamine Uptake Inhibitors Cocaine, Methylphenidate, and Mazindol as a Function of a DAT Transmembrane 1 Aspartic Acid Residue

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Effects of Muscarinic M₁Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

Effects of Muscarinic M₁Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats