The novel antagonist, S33084, and GR218,231 interact selectively with cloned and native, rat dopamine D3 receptors as compared with native, rat dopamine D2 receptors

doi:10.1016/S0014-2999(00)00149-7

European Journal of Pharmacology

Volume 394, Issue 1, 7 April 2000, Pages 47-50

https://doi.org/10.1016/S0014-2999(00)00149-7 Get rights and content

Abstract

The novel benzopyranopyrrole, S33084 ((3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide)), and the aminotetralin derivative, GR218,231 (2(R,S)-(di-n-propylamino)-6-(4-methoxyphenylsulfonylmethyl)-1,2,3,4-tetrahydro naphthalene), displayed high affinity at cloned, rat dopamine D₃ receptors (pK_is of 8.72 and 8.67, respectively), as well as dopamine D₃ receptors in rat olfactory tubercle (8.62 and 8.94, respectively). In contrast, they showed low affinities at striatal dopamine D₂ receptors (6.82 and 6.64, respectively). Unlike S33084 and GR218,231, the arylpiperazine, L741,626 (4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol), showed lower affinity for cloned (6.46) and native (6.92) dopamine D₃ receptors than for striatal dopamine D₂ receptors (7.52). S33084, GR218,231 and L741,626 should prove useful tools for exploration of the functional roles of dopamine D₃ vs. dopamine D₂ receptors.

Introduction

Although transgenic and antisense strategies have provided important insights into functional roles of dopamine D₃ compared with dopamine D₂ receptors Baik et al., 1995, Accili et al., 1996, Tepper et al., 1997, Ekman et al., 1998, there remains a need for selective dopamine D₃ receptor antagonists as experimental tools and — potentially — therapeutic agents Levant, 1997, Wustrow and Wise, 1997. While several, preferential antagonists at dopamine D₃ receptors have been described, some, such as the benzamide, nafadotride, and the aminoindane, U99194 ({5,6-dimethoxy-indan-2-yl) dipropylamine}), show only limited (≤10-fold) selectivity versus dopamine D₂ (and other) receptors Sautel et al., 1995, Audinot et al., 1998, Haadsma-Svensson and Svensson, 1998. Although more selective, the arylpipazine, GR103,691({4′-acetyl-N-{4-[(2-methoxy-phenyl)-piperazin-1-yl]-butyl}-biphenyl-4-carboxamide), displays significant affinity for serotonin 5-HT_1A receptors and α₁-adrenoceptors and only poor bioavailability Murray et al., 1995, Audinot et al., 1998. Further, while the benzofurane, S14297 ((+)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro-naphto(2,3b)dihydro,2,3-furane]), manifests marked selectivity and satisfactory pharmacokinetics, it retains weak partial agonist activity at cloned human dopamine D₃ and D₂ receptors Millan et al., 1995, Cussac et al., 1999a, Newman-Tancredi et al., 1999. In contrast to the above, the aminotetralin GR218,231 (2(R,S)-(di-n-propylamino)-6-(4-methoxyphenylsulfonylmethyl)-1,2,3,4- tetrahydro naphthalene) (Murray et al., 1996), and the recently identified benzopyranopyrrole, S33084 ((3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide)) (Cussac et al., 1999b, Dubuffet et al., 1999; Millan et al., submitted), unite the desired characteristics of high potency, pronounced selectivity and functional activity in vivo. Further, S33084 shows >200-fold selectivity for human dopamine D₃ receptors vs. all other (>40) sites examined (Cussac et al., 1999b; Millan et al., submitted).

However, in common with other dopamine D₃ receptors antagonists, the affinities of GR218,231 and S33084 have, to date, only been determined at heterologously expressed, cloned, human dopamine D₃ and D₂ receptors Murray et al., 1996, Cussac et al., 1999b, Dubuffet et al., 1999. To underpin the potential utility of GR218231 and S33084 as pharmacological tools, it is important to establish that they similarly act as potent ligands of rat dopamine D₃ receptors. To this end, we determined the affinities of S33084 and GR218,231 at cloned and native rat dopamine D₃ as compared with native dopamine D₂ receptors Gackenheimer et al., 1995, Bancroft et al., 1998. The affinities of S33084 and GR218,231 were compared with those of the preferential dopamine D₂ receptor antagonist, L741,626 (4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol) Kulagowski et al., 1996, Levant, 1997, Bancroft et al., 1998.

Section snippets

Affinities at cloned rat dopamine D₃ and striatal rat dopamine D₂ receptors

Drug affinities at cloned rat dopamine D₃ receptors expressed in Chinese hamster ovary cells and at rat (striatal) dopamine D₂ receptors were determined employing standard protocols described previously (Millan et al., 1995). Competition binding experiments were carried out with [³H]spiperone (0.2 nM). Non-specific binding was defined with (+)-butaclamol (10 μM) and raclopride (10 μM) for cloned rat dopamine D₃ and striatal rat dopamine D₂ sites, respectively.

Affinities at rat olfactory tubercle-localised dopamine D₃ receptors

Olfactory tubercles (1/75, w/v)

Results

At cloned, rat dopamine D₃ receptors, both GR218,231 and S33084 potently displaced [³H]spiperone (Table 1). In distinction, L741,626 showed only modest affinity for these sites. Both 7-OH-DPAT and PD128,907 were potent ligands at cloned, rat dopamine D₃ receptors (Table 1). In rat olfactory tubercle, S33084 and GR218,231 potently displaced [³H]7-OH-DPAT in the presence of GTPγS (100 μM), (Fig. 1 and Table 1). On the other hand, the affinity of L741,626 was modest. The affinities of 7-OH-DPAT

Discussion

In analogy to PD128,907 and other preferential dopamine D₃ receptor agonists employed for radiolabelling of dopamine D₃ sites, 7-OH-DPAT possesses significant affinity for the “high-affinity” state of dopamine D₂ receptors Gackenheimer et al., 1995, Gonzales and Sibley, 1995, Bancroft et al., 1998. The GTP analogue, GTPγS, in decoupling dopamine D₂ receptors from the associated G-protein, suppresses this high-affinity state: that is, it permits the isolation of a GTP-resistant component of [³

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Binding of [³H]PD 128907, a putatively selective ligand for the D₃ dopamine receptor, in rat brain: a receptor binding and quantitative autoradiographic study
Neuropsypharmacology
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Bifeprunox and aripiprazole suppress in vivo VTA dopaminergic neuronal activity via D<inf>2</inf> and not D<inf>3</inf> dopamine autoreceptor activation
2009, Neuroscience Letters
Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D₂ and D₃ dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D_2/3 receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D₂-like agonistic activities [L. Dahan, H. Husum, O. Mnie-Filali, J. Arnt, P. Hertel, N. Haddjeri, Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour, J. Psychopharmacol. (2009)]. In the present electrophysiological study, selective antagonists of D₂ and D₃ receptors were used to further characterize the inhibitory role of bifeprunox and aripiprazole on the D₂ and D₃ receptors in vivo. Administration of bifeprunox (250 μg/kg, i.v.) or aripiprazole (300 μg/kg, i.v.) reduced the firing activity of VTA DA neurons by 40–50%. The bursting activity was reduced by 95% and 77% by bifeprunox and aripiprazole, respectively. Systemic administration of the preferential D₃ receptor antagonist GR218,231 (200 μg/kg, i.v.) did not modify the inhibitory effect of bifeprunox or aripiprazole, either on the firing or on the bursting activity. On the other hand, the preferential D₂ receptor antagonist L741,626 (500 μg/kg, i.v.) completely blocked the inhibitory effect of both bifeprunox and aripiprazole on the VTA DA neuronal activity. The present study shows that bifeprunox and aripiprazole behave as partial D₂, but not D₃, receptor agonists in vivo, inhibiting the firing activity (preferentially the phasic activity) of VTA DA cells.
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Short communicationThe novel antagonist, S33084, and GR218,231 interact selectively with cloned and native, rat dopamine D3 receptors as compared with native, rat dopamine D2 receptors

Abstract

Introduction

Section snippets

Affinities at cloned rat dopamine D3 and striatal rat dopamine D2 receptors

Affinities at rat olfactory tubercle-localised dopamine D3 receptors

Results

Discussion

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Eur. J. Pharmacol.

A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice

Proc. Natl. Acad. Sci. U. S. A.

A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists, (+)-S 14297, nafadotride, GR 103,691 and U 99194

J. Pharmacol. Exp. Ther.

Parkisonian-like locomotor impairment in mice lacking dopamine D2 receptors

Lett. Nat.

Binding of [3H]PD 128907, a putatively selective ligand for the D3 dopamine receptor, in rat brain: a receptor binding and quantitative autoradiographic study

Neuropsypharmacology

Human dopamine D3 receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism

Mol. Pharmacol.

S33084, a novel, potent and selective benzopyrano-pyrrolidine antagonist and radioligand at dopamine D3 receptors

Soc. Neurosci.

Central administration of dopamine D3 receptor antisense to rat: effects on locomotion, dopamine release and [3H] spiperone binding

Naunyn-Schmiedeberg's Arch. Pharmacol.

[3H]-Quinelorane binds to D2 and D3 dopamine receptors in the rat brain

J. Pharmacol. Exp. Ther.

Short communication
The novel antagonist, S33084, and GR218,231 interact selectively with cloned and native, rat dopamine D₃ receptors as compared with native, rat dopamine D₂ receptors

Affinities at cloned rat dopamine D₃ and striatal rat dopamine D₂ receptors

Affinities at rat olfactory tubercle-localised dopamine D₃ receptors

A targeted mutation of the D₃ dopamine receptor gene is associated with hyperactivity in mice

A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D₃ receptor antagonists, (+)-S 14297, nafadotride, GR 103,691 and U 99194

Parkisonian-like locomotor impairment in mice lacking dopamine D₂ receptors

Binding of [³H]PD 128907, a putatively selective ligand for the D₃ dopamine receptor, in rat brain: a receptor binding and quantitative autoradiographic study

Human dopamine D₃ receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism

S33084, a novel, potent and selective benzopyrano-pyrrolidine antagonist and radioligand at dopamine D₃ receptors

Central administration of dopamine D₃ receptor antisense to rat: effects on locomotion, dopamine release and [³H] spiperone binding

[³H]-Quinelorane binds to D₂ and D₃ dopamine receptors in the rat brain