Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SAR

Medicinal Chemistry, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 03/2007; 17(3):745-9. DOI: 10.1016/j.bmcl.2006.10.076
Source: PubMed


A series of analogues of the dopamine D2 receptor antagonist L741,626 were synthesized and evaluated for binding and function at D2 family receptor subtypes. Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity.

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Available from: Amy H. Newman, May 12, 2014
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    • "The dopamine D 3 receptor antagonists, SB277,011 and S33084, have high selectivity for the dopamine D 3 over the D 2 receptor (over 100-fold in ligand binding studies, Millan et al, 2000a, b). Furthermore, L741,626 is currently the most preferential D 2 receptor antagonist available, having between 15-and 40-fold selectivity for the rat dopamine D 2 relative to the D 3 receptor in radioligand binding (Cussac et al, 2000; Kulagowski et al, 1996; Millan et al, 2004; Reavill et al, 2000) and functional assays (Grundt et al, 2007), with both native and cloned receptors. No data are currently available in the mouse to confirm a similar selectivity. "
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    ABSTRACT: Dopamine D(3) receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D(3) vs D(2) receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D(3) receptor antagonist, S33084 (0.04-0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D(3) receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D(2) receptor antagonist, L741,626 (0.16-5.0 mg/kg), or with the dopamine D(3) agonist, PD128,907 (0.63-40 μg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of S33084 (2.5 μg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63-2.5 μg/side) improvement in NOR, while intra-striatal injection (2.5 μg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63-2.5 μg/side) impairment of NOR. These observations suggest that blockade of dopamine D(3) receptors enhances both SND and NOR, whereas D(3) receptor activation or antagonism of dopamine D(2) receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D(3) receptor antagonism.
    Full-text · Article · Feb 2012 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "The goal of the present study was to help differentiate the contributions of D3 and D2 receptors to cocaine's abuserelated effects by comparing the modulation of cocaine-induced behaviors by the novel D3-preferring antagonist PG01037 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans- but-2-enyl)-4-pyridine-2-ylbenzamide)] (Grundt et al., 2005) and the D2-preferring antagonist L-741626 [3-[4-(4-chloro- phenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole] (Grundt et al., 2007a). PG01037 preferentially occupies D3-rich regions over D2-rich regions as illustrated by pharmacologic magnetic resonance imaging (Grundt et al., 2007b) and is at least twice as D3-selective compared with other antagonists such as NGB2904. "
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    ABSTRACT: Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferring antagonist PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin- 1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl] and the D2-preferring antagonist L-741626 [3-[4-(4-chlorophenyl)-4- hydroxypiperidin-1-yl]methyl-1H-indole] attenuated several behavioral effects of cocaine in squirrel monkeys. Quantitative observational studies established doses of each antagonist that did not produce untoward effects, which were used in subsequent comparisons. In addition, the ability of the D3-preferring agonist PD128907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H- imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate] to reproduce cocaine's discriminative stimulus (DS) and priming effects were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine- and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine.
    Preview · Article · Aug 2010 · Journal of Pharmacology and Experimental Therapeutics
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    • "The training dose of pramipexole was 0.1 mg/kg, the dose that elicits maximal levels of the D3-mediated behavior of yawning; and the training dose of sumanirole was 1.0 mg/kg, a dose that has been shown to induce a robust D2-mediated hypothermia response (Collins et al. 2007). The D2-preferring antagonist L-741,626 (D2/D3 selectivity of 15-fold in vitro, Grundt et al. 2007a), the D3-preferring antagonist PG01037 (D3/D2 selectivity of 133-fold in vitro, Grundt et al. 2007b), and the nonselective D2/ D3/D4 antagonist haloperidol was used to determine the receptor subtypes mediating the pramipexole and sumanirole discriminative stimuli. Additional compounds tested include cocaine and the D3-preferring agonists quinpirole and 7-OH-DPAT. "
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    ABSTRACT: Rationale Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors. Objectives The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists. Materials and methods Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole. Results Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Conclusions Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role.
    Full-text · Article · Mar 2009 · Psychopharmacology
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