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

Glowa, John R.; Fantegrossi, William E.; Lewis, David B.; Matecka, Dorota; Rice, Kenner C.; Rothman, Richard B.

doi:10.1021/jm960551t

Cited by 68 publications

(89 citation statements)

References 7 publications

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“…118 One study investigated a decanoate derivative of one of the oxygenated GBR 12909 analogs described above in sustaining decreases in cocaine-maintained responding in rhesus monkeys. 132 The results of this study showed that a single injection of this agent provided sustained and selective (over food) suppression of cocaine-maintained responding for nearly 30 days. Because of its (several day) slow onset and long duration of action, it was suggested that the abuse liability of such an agent would be low as well.…”

Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 68%

“…Because of its (several day) slow onset and long duration of action, it was suggested that the abuse liability of such an agent would be low as well. 132 Preliminary behavioral evaluation of additional GBR 12909 analogs have demonstrated that some of these compounds are not cocaine-like or GBR 12909-like in locomotor activity or drug discrimination studies. 122 These studies more closely resemble those behavioral studies that we have conducted on both the benztropines and rimcazoles wherein most of these ligands do not appear to behave like cocaine, despite binding with high affinity to the DAT.…”

Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 99%

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Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Newman

Kulkarni

2002

Medicinal Research Reviews

107

144

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In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine-like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure-activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related to the differing pharmacological actions of these compounds, in vivo. These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine-abuse therapeutics.

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Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 68%

Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 99%

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Newman

Kulkarni

2002

Medicinal Research Reviews

107

144

View full text Add to dashboard Cite

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“…If this hypothesis is correct, then GBR12909, or a similarly acting agent, such as its long-acting decanoate derivative (Glowa et al, 1996), may be a candidate treatment agent for METH addiction, since it would block the acute euphoric effects of METH as well as METHinduced neurotoxicity (Seiden et al, 1993). Fig.…”

Section: Discussionmentioning

confidence: 99%

GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [11C]raclopride continuous infusion PET scans

Villemagne

Wong

Yokoi

et al. 1999

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Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange mechanism. Preclinical research supports the hypothesis that elevations of mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high affinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases in mesolimbic DA. The present study determined the ability of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [(11)C]raclopride continuous infusion positron emission tomography (PET) scans in two Papio anubis baboons. [(11)C]Raclopride was given in a continuous infusion paradigm resulting in a flat volume of distribution vs. time for up to 45 min postinjection. At that time, a 1.5 mg/kg amphetamine i.v. bolus was administered which caused a significant (30.3%) reduction in the volume of distribution (V(3)"). The percent reduction in the volume of distribution and, hence, a measure of the intrasynaptic DA release ranged between 22-41%. GBR12909 (1 mg/kg, slow i.v. infusion) was administered 90 min before the administration of the radiotracer. The comparison of the volume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiments suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the DA hypothesis is correct, a potential treatment agent for cocaine and methamphetamine abuse. Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR12909 such as a decanoate derivative.

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“…A single molecular entity which would block the transport of METH at all three biogenic amine transporters might function to neurochemically neutralize METH. Such an agent would ideally be a high-affinity slowly dissociating agent at all three transporters and also be amenable to formulation as a long-acting depot medication, such as has been accomplished with an analog of GBR12909 (Glowa et al, 1996). We anticipate that a medication meeting these requirements would not only neutralize the neurochemical effects of METH, but would also contribute anticraving and antidepressant effects, facilitating relapse prevention.…”

Section: Introductionmentioning

confidence: 99%

Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse

Rothman

Partilla

Baumann

et al. 2000

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The abuse of methamphetamine (METH) and other amphetamine-like stimulants is a growing problem in the United States. METH is a substrate for the 12-transmembrane proteins which function as transporters for the biogenic amines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Increased release of CNS DA is thought to mediate the addictive effects of METH, whereas increased release of NE in both the peripheral and CNS is thought to mediate its cardiovascular effects. The neurotoxic effects of METH on both dopaminergic and serotonergic nerves requires the transport of METH into the nerve terminals. Thus, transport of METH into nerve terminals is the crucial first step in the production of METH-associated pharmacological and toxicological effects. A single molecular entity which would block the transport of METH at all three biogenic amine transporters might function to neurochemically neutralize METH. This agent would ideally be a high-affinity slowly dissociating agent at all three transporters, and also be amenable to formulation as a long-acting depot medication, such as has been accomplished with an analog of GBR12909. As a first step towards developing such an agent, we established an in vitro assay which selectively detects transporter substrates and used this assay to profile the ability of a lead compound, indatraline, to block the releasing effects of METH and MDMA at the DA, 5-HT, and NE transporters. The major finding reported here is that indatraline blocks the ability of METH and MDMA to release these neurotransmitters.

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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

Cited by 68 publications

References 7 publications

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [11C]raclopride continuous infusion PET scans

Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse

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