N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl}arylcarboxamides as novel dopamine D3 receptor antagonists

Newman, Amy Hauck; Cao, Jianjing; Bennett, Christina; Robarge, Michael J.; Freeman, Rebekah A.; Luedtke, Robert R.

doi:10.1016/s0960-894x(03)00389-5

Cited by 58 publications

(82 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SB-277011A is a highly potent and selective D 3 receptor antagonist that has 80-to 100-fold selectivity for D 3 over other DA receptors and 100-fold selectivity over 180 other receptors, enzymes, ion channels, and transporters in the central nervous system (Reavill et al 2000;Stemp et al 2000;Micheli and Heidbreder 2006;Heidbreder et al, unpublished data). Similarly, the novel D 3 receptor antagonist NGB 2904 also has >150-fold selectivity for primate D 3 over primate D 2 receptors, >800-fold selectivity for rat D 3 vs rat D 2 receptors, and >5,000-fold selectivity over D 1 , D 4 , and D 5 receptors (Yuan et al 1998;Newman et al 2003). These data suggest that the attenuation of METH-enhanced BSR by SB-277011A or NGB 2904 observed in the present study is most likely mediated by action on brain DA D 3 receptors in vivo.…”

Section: Receptor Antagonists Have Anti-addiction Action Withoutmentioning

confidence: 99%

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

Spiller

Peng

et al. 2007

Psychopharmacology

View full text Add to dashboard Cite

Rationale-We have previously reported that selective antagonism of brain D 3 receptors by SB-277011A or NGB 2904 significantly attenuates cocaine-or nicotine-enhanced brain stimulation reward (BSR).Objective-In the present study, we investigated whether the selective D 3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D 3 agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR.Materials and methods-Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a ratefrequency curve shift paradigm was used to measure brain-reward threshold (θ 0 ). © Springer-Verlag 2007Correspondence to: Zheng-Xiong Xi. Conflict of interest statementThere are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2013 July 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptResults-METH (0.1-0.65 mg/kg, i.p.) dose-dependently lowered (~10-50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1-1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1-5 mg/kg) dose-dependently attenuated METHenhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation-response curve to the right (inhibited BSR itself) in the presence or absence of METH.Conclusions-Selective antagonism of D 3 receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D 3 and non-D 3 receptors. These findings support a potential use of selective D 3 receptor antagonists for the treatment of METH addiction.

show abstract

Section: Receptor Antagonists Have Anti-addiction Action Withoutmentioning

confidence: 99%

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

Spiller

Peng

et al. 2007

Psychopharmacology

View full text Add to dashboard Cite

show abstract

“…Furthermore, the effect of the selective D 3 receptor antagonist NGB-2904 [236,313] has recently been examined in animal models of addiction [309]. It has been reported that, using baculovirus expression of rat DA receptors in vitro, the selectivity of NGB-2904 for D 3 vs. D 2 is 830 as determined by D 2 and D 3 receptor binding and use of the radioligand [ 125 I]-IABN [214]. NGB-2904 was also shown to be a functional antagonist in the mitogenesis assay using human D 3 -transfected CHO cells [236].…”

Section: Summary Of Effects Of Sb-277011-a On Addictive Drug Actionmentioning

confidence: 99%

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

Heidbreder

Gardner

et al. 2005

Brain Research Reviews

305

249

View full text Add to dashboard Cite

The cDNA for the dopamine D 3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D 3 receptors, as well as D 3 receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D 3 receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D 3 receptors. The interpretation of results from studies using mixed D 2 /D 3 agonists and/or antagonists is problematic because these agents have low selectivity for D 3 over D 2 receptors and it is likely that their actions are primarily related to D 2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D 3 receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D 3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D 3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D 3 receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stressinduced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D 3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction.

show abstract

“…Consequently, this raises the issue of whether the presently observed attenuating effects of NGB 2904 in these three behavioral paradigms might be attributable to D 1 or D 2 receptor-selective antagonism rather than to D 3 receptor-selective antagonism. We believe that is unlikely, because (1) multiple lines of in vitro evidence indicate that NGB 2904 is a highly selective D 3 receptor antagonist (Yuan et al, 1998;Robarge et al, 2001;Newman et al, 2003Newman et al, , 2005; see Introduction); (2) in the BSR paradigm, D 1 -and D 2 -preferring DA receptor antagonists inhibit brain reward functions, in a manner opposite to the brain reward enhancement produced by addictive drugs (Stein and Ray, 1960;Stein, 1962;Wise, 1982;Panagis and Spyraki, 1996;Gardner, 2005), while selective blockade of DA D 3 receptors by either NGB 2904 or SB-277011A does not alter electrical brain reward thresholds (Vorel et al, 2002;Campos et al, 2003Campos et al, , 2004; and finally (3) NGB 2904 does not significantly alter locomotor activity at the dose range tested in the present study (Newman et al, 2005), again unlike D 1 or D 2 receptor antagonists.…”

Section: Ngb 2904's Selective Blockade Of Da D 3 Receptorsmentioning

confidence: 99%

“…This compound has structural similarity to BP-897 (Pilla et al, 1999;Wood et al, 2000;Wicke and Garcia-Ladona, 2001), and binds with high affinity to cloned primate D 3 receptors (K i 1.4 nM) (Yuan et al, 1998;Robarge et al, 2001). NGB 2904 is reported to have 155-fold selectivity for primate D 3 over primate D 2 receptors, and 4800-fold selectivity for rat D 3 vs D 2 receptors (Yuan et al, 1998;Newman et al, 2003). Also, it has 45000-fold selectivity over D 1 , D 4 , and D 5 receptors and 200-to 600-fold selectivity over a 1 and 5HT 2 receptors (Yuan et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

Newman

Gilbert

et al. 2005

Neuropsychopharmacol

Self Cite

146

177

View full text Add to dashboard Cite

Accumulating evidence indicates that dopamine (DA) D 3 receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D 3 -selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long-Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1-10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D 3 -selective antagonist NGB 2904 attenuates cocaine's rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.

show abstract

N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl}arylcarboxamides as novel dopamine D3 receptor antagonists

Cited by 58 publications

References 20 publications

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

Contact Info

Product

Resources

About