Interactions of ligands with active and inactive conformations of the dopamine D2 receptor

Malmberg, Åsa; Mohell, Nina; Höök, Berit Backlund; Johansson, Anette M.; Hacksell, Uli; Nordvall, Gunnar

doi:10.1016/s0014-2999(98)00047-8

Cited by 28 publications

(33 citation statements)

References 20 publications

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“…High and D 2 Low , respectively) (Sibley et al 1982;Malmberg et al 1998;Gazi et al 2003a). This state of affairs is traditionally explained by the "ternary complex" model (De Lean et al 1980; further extended by Samama et al 1993) wherein GPCRs adopt a high agonist affinity state/ conformation when they couple to their cognate G proteins.…”

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

“…However, this phenomenon is not readily observed at a lower receptor expression and/or when the response is measured at the level of naïve G protein activation, i.e., early on in the response pathway (Gardner et al 1996;Malmberg et al 1998;Vanhauwe et al 1999;Gilliland and Alper 2000;Wilson et al 2001;Pauwels et al 2001a;Jordan et al 2007b;Masri et al 2008).…”

Section: Functional Assaysmentioning

confidence: 99%

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Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Vauquelin

Bostoen

Vanderheyden

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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Drug-receptor interactions are traditionally quantified in terms of affinity and efficacy, but there is increasing awareness that the drug-on-receptor residence time also affects clinical performance. While most interest has hitherto been focused on slow-dissociating drugs, D(2) dopamine receptor antagonists show less extrapyramidal side effects but still have excellent antipsychotic activity when they dissociate swiftly. Fast dissociation of clozapine, the prototype of the "atypical antipsychotics", has been evidenced by distinct radioligand binding approaches both on cell membranes and intact cells. The surmountable nature of clozapine in functional assays with fast-emerging responses like calcium transients is confirmatory. Potential advantages and pitfalls of the hitherto used techniques are discussed, and recommendations are given to obtain more precise dissociation rates for such drugs. Surmountable antagonism is necessary to allow sufficient D(2) receptor stimulation by endogenous dopamine in the striatum. Simulations are presented to find out whether this can be achieved during sub-second bursts in dopamine concentration or rather during much slower, activity-related increases thereof. While the antagonist's dissociation rate is important to distinguish between both mechanisms, this becomes much less so when contemplating time intervals between successive drug intakes, i.e., when pharmacokinetic considerations prevail. Attention is also drawn to the divergent residence times of hydrophobic antagonists like haloperidol when comparing radioligand binding data on cell membranes with those on intact cells and clinical data.

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Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

Section: Functional Assaysmentioning

confidence: 99%

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Vauquelin

Bostoen

Vanderheyden

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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“…1992; Harley et al . 1995; Malmberg et al . 1998) and correlations have been claimed between the K l / K h ratio and the maximal effects of agonists or their relative efficacies in functional assays.…”

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confidence: 99%

Mechanisms of ligand binding and efficacy at the human D_2(short) dopamine receptor

Payne

Johansson

Strange

2002

Journal of Neurochemistry

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Mechanisms of ligand binding and receptor activation for the human D 2(short) dopamine receptor have been probed using two homologous series of monohydroxylated and dihydroxylated agonists (phenylethylamines and 2-dipropylaminotetralins). In ligand binding studies, the majority of compounds exhibited competition curves versus [ 3 H]spiperone that were best fitted using a two site binding model. The compounds had different abilities (potencies and maximal effects) to stimulate [ 35 S]GTPcS binding and to inhibit forskolin-stimulated cAMP accumulation. From the data it can be concluded that: (i) the ability of an agonist to stabilize receptor/G protein coupling can be used to predict agonist efficacy for some groups of compounds (2-dipropylaminotetralins) but not for others (phenylethylamines); (ii) the receptor may be activated by unhydroxylated compounds; (iii) single hydroxyl groups or pairs of hydroxyl groups on the agonist may contribute to binding affinity, potency and efficacy; and (iv) for the 2-dipropylaminotetralin series two modes of agonist/receptor interaction have been identified associated with different relative efficacy.

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“…37 The [ 3 H]raclopride(D 2 )/[ 3 H]quinpirole(D 2 ) ratios ranged between 1 and 8, indicating low intrinsic activities of the compounds. 10,40 These ratios may be compared with those of the endogenous DA (300) and the DA D 2 receptor antagonist haloperidol (4) ( Table 2). The low agonist activities of the novel compounds were corroborated by their DA D 2 and D 3 receptor-mediated effects on basal [ 35 S]GTPγS binding (Table 3).…”

Section: Resultsmentioning

confidence: 99%

Novel (R)-2-Amino-5-fluorotetralins: Dopaminergic Antagonists and Inverse Agonists

et al. 1996

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A series of secondary and tertiary N-alkyl derivatives of (R)-2-amino-5-fluorotetralin have been prepared. The affinities of the compounds for [3H]raclopride-labeled cloned human dopamine (DA) D2 and D3 receptors as well as [3H]-8-OH-DPAT-labeled rat hippocampal 5-HT1A receptors were determined. In order to selectively determine affinities for the high-affinity agonist binding site at DA D2 receptors, the agonist [3H]quinpirole was used. The intrinsic activities of the compounds at DA D2 and D3 receptors were evaluated in a [35S]GTP gamma S binding assay. The novel compounds were characterized as dopaminergic antagonists or inverse agonists. The antagonist (R)-2-(butylpropylamino)-5-fluorotetralin (16) bound with high affinity (Ki = 4.4 nM) to the DA D3 receptor and was the most D3-selective compound (10-fold). (R)-2-[[4-(8-Aza-7, 9-dioxospiro[4.5]decan-8-yl)butyl]propylamino]-5-fluorote tralin (18) bound with very high affinity to both DA D3 and 5-HT1A receptors (Ki = 0.2 nM) and was also characterized as a dopaminergic antagonist. (R)-2-(Benzylpropylamino)-5-fluorotetralin (10) behaved as an inverse agonist at both DA D2 and D3 receptors. It decreased the basal [35S]GTP gamma S binding and potently inhibited the DA-stimulated [35S]GTP gamma S binding. It is apparent that the intrinsic activity of a 2-aminotetralin derivative may be modified by varying the N-alkyl substituents.

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Interactions of ligands with active and inactive conformations of the dopamine D2 receptor

Cited by 28 publications

References 20 publications

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Mechanisms of ligand binding and efficacy at the human D_2(short) dopamine receptor

Novel (R)-2-Amino-5-fluorotetralins: Dopaminergic Antagonists and Inverse Agonists

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Interactions of ligands with active and inactive conformations of the dopamine D2 receptor

Cited by 28 publications

References 20 publications

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Mechanisms of ligand binding and efficacy at the human D2(short) dopamine receptor

Novel (R)-2-Amino-5-fluorotetralins: Dopaminergic Antagonists and Inverse Agonists

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Product

Resources

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Mechanisms of ligand binding and efficacy at the human D_2(short) dopamine receptor