Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA et al. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 20: 612-627

Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, United States
Neuropsychopharmacology (Impact Factor: 7.05). 07/1999; 20(6):612-27. DOI: 10.1016/S0893-133X(98)00099-2
Source: PubMed


OPC-14597 {aripiprazole; 7-(-4(4-(2,3-dichlorophenyl)-1-piperazinyl) butyloxy)-3,4-dihydro-2(1H)-quinolinone} is a novel candidate antipsychotic that has high affinity for striatal dopamine D2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-1451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT6 and 5HT7 receptors. All three compounds exhibited highest affinity for D2L and D2S receptors relative to the other cloned receptors examined. Both OPC-4392 and OPC-14597 demonstrated dual agonist/antagonist actions at D2L receptors, although the metabolite DM-1451 behaved as a pure antagonist. These data suggest that clinical atypicality can occur with drugs that exhibit selectivity for D2L/D2S rather than D3 or D4 receptors, and raise the possibility that the unusual profile of OPC-14597 in vivo (presynaptic agonist and postsynaptic antagonist) may reflect different functional consequences of this compound interacting with a single dopamine receptor subtype (D2) in distinct cellular locales.


Available from: Mechelle M Lewis
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    • "In contrast to haloperidol, quetiapine (1) has only transient D 2 receptor occupancy [22], (2) exhibits higher affinity 5HT 2A receptor binding than affinity for D 2 receptor [ratio of K i values for 5HT 2A / D 2 receptors are clozapine: 0.05; quetiapine: 0.75; haloperidol: 51] [21], and (3) is a 5HT 1A receptor partial agonist [23]. In a similar fashion, the atypical antipsychotic medication aripiprazole (1) is a D 2 receptor partial agonist [24] [25], (2) is a high affinity 5HT 2A receptor functional antagonist [25], and (3) is a 5HT 1A receptor partial agonist [25]. These three independent pharmacological activities would each be expected to limit extracellular glutamate and subsequent neurotoxicity for both quetiapine and aripiprazole relative to haloperidol. "
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    ABSTRACT: We hypothesize the interaction between antipsychotic medications and regulation of extracellular glutamate which has gone largely unnoticed in the medical community has significant clinical importance. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate because they exert antagonist effects on dopamine D(2) and serotonin 5HT(1A) receptors. In contrast, serotonin 5HT(2A) receptor antagonists inhibit glutamate release. Glutamate is potentially excitotoxic through effects on ionotropic receptor channels and may exert synergistic effects with other neurotoxic pathways. In contrast to typical antipsychotic drugs, pharmacological properties of atypical antipsychotic medications at dopamine D(2), serotonin 5HT(1A) and 5HT(2A) receptors limit extracellular glutamate and may theoretically be neuroprotective in certain clinical settings. In this review we discuss three common clinical settings in which typical antipsychotic medications may potentiate neurotoxicity by elevating extracellular glutamate. The most common clinical setting, hypoglycemia during combined use of antipsychotic medications and insulin, presents a theoretical risk for 35 million diabetic patients worldwide using antipsychotic medications. Antipsychotic medication treatment during hypoxic episodes in the intensive care unit and following traumatic brain injury are two other common clinical settings in which this interaction poses theoretical risk. Further study is needed to test hypothesized risk mechanisms, and determine clinical and epidemiological consequences of these exposures.
    Medical Hypotheses 12/2012; 80(3). DOI:10.1016/j.mehy.2012.11.042 · 1.07 Impact Factor
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    • "One of the earliest demonstrations of functional selectivity was with the dopamine D 2 receptor (Lawler et al., 1994, 1999). In particular, studies with a series of relatively rigid, conformationally restrained D 2 ligands showed extreme bias in signaling, in some cases as extreme as full agonist and pure antagonist (Mottola et al., 1991, 2002; Kilts et al., 2002; Gay et al., 2004). "
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    ABSTRACT: Although functional selectivity is now widely accepted, the molecular basis is poorly understood. We have studied how aspects of transmembrane region 5 (TM5) of the dopamine D(2L) receptor interacts with three rationally selected rigid ligands (dihydrexidine, dinapsoline, and dinoxyline) and the reference compounds dopamine and quinpirole. As was expected from homology modeling, mutation of three TM5 serine residues to alanine (S5.42A, S5.43A, S5.46A) had little effect on antagonist affinity. All three mutations decreased the affinity of the agonist ligands to different degrees, S5.46A being somewhat less affected. Four functions [adenylate cyclase (AC), extracellular signal-regulated kinase 1/2 phosphorylation (MAPK), arachidonic acid release (AA), and guanosine 5'-O-(3-thio)triphosphate binding (GTPγS)] were assessed. The intrinsic activity (IA) of quinpirole was unaffected by any of the mutations, whereas S5.42A and S5.46A mutations abolished the activity of dopamine and the three rigid ligands, although dihydrexidine retained IA at MAPK function only with S5.42A. Remarkably, S5.43A did not markedly affect IA for AC and MAPK for any of the ligands and eliminated AA activity for dinapsoline and dihydrexidine but not dinoxyline. These data suggest that this mutation did not disrupt the overall conformation or signaling ability of the mutant receptors but differentially affected ligand activation. Computational studies indicate that these D(2) agonists stabilize multiple receptor conformations. This has led to models showing the stabilized conformations and interhelical and receptor-ligand contacts corresponding to the different activation pathways stabilized by various agonists. These data provide a basis for understanding D(2L) functional selectivity and rationally discovering functionally selective D(2) drugs.
    Molecular pharmacology 03/2012; 81(6):820-31. DOI:10.1124/mol.111.075457 · 4.13 Impact Factor
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    • "Indeed, different agonists have been proposed to stabilize unique receptor conformations with different abilities to couple to G proteins and downstream effectors, a process denoted as " agonist directed-trafficking " (Kenakin 1996, 2003; Nickolls and Strange 2004). This could lead to divergent results when comparing the in vitro functional characteristics of D 2 receptor agonists and partial agonists in different assays and even hinder the detection of the latter in certain screening studies (Lawler et al. 1999; Jordan et al. 2007a). "
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    ABSTRACT: 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.
    Archiv für Experimentelle Pathologie und Pharmakologie 02/2012; 385(4):337-72. DOI:10.1007/s00210-012-0734-2 · 2.47 Impact Factor
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