Dopamine D2 Receptor Partial Agonist Research Articles

Characterization of PG‐619, a dopamine D3 receptor partial agonist, on cocaine self‐administration and drug‐elicited yawning in rhesus monkeys

The dopamine D3 receptor is a promising target for the development of novel treatment agents for addiction due to its restricted expression in limbic brain regions and involvement in reinforcement pathways (Newman et al., 2005). The present study examined the effects of PG‐619, a D3 receptor partial agonist, with 100‐fold selectivity for the D3 over D2 receptors (Grundt et al., 2007), on cocaine self‐administration (SA) and yawning in male rhesus monkeys with an extensive cocaine history (n=3). Monkeys self‐administered cocaine (0.003‐0.3 mg/kg) under a fixed‐ratio 30 schedule during daily 2‐hr sessions. Prior work found CJB 090, a D3 partial agonist with 60‐fold D3 selectivity, decreased cocaine‐maintained responding (Martelle et al., 2007). Acute doses of PG‐619 (0.1 ‐ 1.0 mg/kg, i.v., 10 min presession) did not significantly affect cocaine SA; higher doses of PG‐619 are currently being evaluated. In vivo potency of PG‐619 to elicit yawning was also examined. As with CJB 090, no doses of PG‐619 (0.1 ‐ 1.0 mg/kg) elicited yawning. The preliminary findings support prior work that D3 partial agonists do not have D3 agonist effects in vivo. Furthermore, the findings suggest greater selectivity of D3 over D2 receptors may result in substantial decreases in potency to affect cocaine SA, although bioavailability and pharmacokinetic factors may contribute to the behavioral profiles of these drugs. DA 12460 and NIDA‐IRP.

Aripiprazole for Patients with Schizophrenia and Schizoaffective Disorder: An Open-Label, Randomized, Study Versus Haloperidol

Aripiprazole, a dopamine D2 receptor partial agonist, has also partial agonist activity at serotonin (5-HT)1A receptors and antagonist activity at 5-HT2A receptors. In this 8-week, multicenter, randomized, parallel-group, open-label, flexible-dose study, patients diagnosed with schizophrenia or schizoaffective disorder were randomized to aripiprazole 15-30 mg/day or haloperidol 10-15 mg/day. Patients treated with both aripiprazole and haloperidol improved from baseline in Positive and Negative Syndrome Scale total, positive, and negative scores as well as in Clinical Global Impressions scores (all P<.001). At the end of the study, the percentage of patients classified as responders--according to >or=40% reduction in the Positive and Negative Syndrome Scale negative subscale score--was significantly higher in the aripiprazole group (20%) than in the haloperidol group (0%) (P<.05). Additionally, a higher number of patients receiving haloperidol required more anticholinergic medications (P<.001) than aripiprazole-treated patients, whereas more aripiprazole (45.5%) than haloperidol-treated patients (12.9%) required benzodiazepines (P=.002). At endpoint, rates of preference of medication were higher in the aripiprazole group (63.2%) than in the haloperidol group (21.7%), as expressed by patients and caregivers (P=.001). Aripiprazole and haloperidol had similar efficacy in terms of reduction of overall psychopathology. Although aripiprazole has been demonstrated to be superior concerning negative symptoms and in terms of tolerability (extrapyramidal symptoms) and preferred by patients and caregivers than haloperidol, significantly more aripiprazole-treated patients required benzodiazepines.

Treatment of the symptoms of Huntington's disease: Preliminary results comparing aripiprazole and tetrabenazine

Aripiprazole (AP), a dopamine (DA) D(2) receptor partial agonist, has recently been used to reduce schizophrenic symptoms, while tetrabenazine (TBZ), a DA depletor, has been used to treat hyperkinesias in Huntington's disease (HD). The aim of this study is to define the role of AP on chorea, motor performance, and functional disability, and to compare the effects of AP vs. TBZ in a small study of six patients with HD. Both AP and TBZ increased the Unified Huntington's Disease Rating Scale (UHDRS) chorea score in a similar way. However, AP caused less sedation and sleepiness than TBZ and was better tolerated by the patients on the trial. Moreover, AP showed a slight but not significant improvement of depression in the patients as compared to TBZ. A larger group of patients and a longer period of observation are an important prerequisite for further evaluations of AP's therapeutic use.

Decrease in tobacco consumption after treatment with topiramate and aripiprazole: a case report

IntroductionA large part of research into drug addiction focuses on mesolimbic dopamine circuitry; however, both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and/or kainate and dopamine D2 receptors can play a role in maintaining the established addiction.Case presentationWe report the case of a 34-year-old man who compulsively smoked 80 to 100 cigarettes each day. After receiving treatment with topiramate and aripiprazole, his tobacco consumption was dramatically reduced.ConclusionAlpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and/or kainate blocking agents and a dopamine D2 receptor partial agonist may be novel instruments for nicotine abuse disorders.

Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour

The atypical antipsychotic bifeprunox is a partial dopamine D(2) and 5-HT(1A) receptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock-induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20-50%) firing of dopamine neurons. Interestingly, bursting activity was markedly reduced (by 70-100%), bursting being associated with a larger synaptic dopamine release than single spike firing. Both ligands reduced inhibition of firing rate induced by the full dopamine receptor agonist apomorphine, whereas the D(2) receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D(2)-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT(1A) receptor antagonist WAY-100,635 prevented their effects. In the USV test of anxiolytic-like activity, bifeprunox had higher potency than aripiprazole to reduce vocalisations. Both WAY-100,635 and haloperidol reversed the effects of both agonists. The present in-vivo study shows that bifeprunox is a potent partial D(2)-like and 5-HT(1A) receptor agonist reducing preferentially the phasic activity of dopamine neurons. Thus, bifeprunox would be expected to be an effective compound against positive and negative symptoms of schizophrenia.

Modulation of the Reinforcing and Discriminative Stimulus Effects of Cocaine by the Dopamine D3 Receptor Partial Agonist CJB 090 [N‐(4‐(4‐(2,3‐Dichlorophenyl)piperazin‐4‐(pyridine‐2‐yl)benzamide] in Squirrel Monkeys

Dopamine D3 receptor mechanisms have been implicated repeatedly in the behavioral effects of cocaine. This study evaluated the effects of the D3 receptor partial agonist CJB 090 in monkeys trained to: 1) discriminate cocaine from vehicle, 2) self‐administer cocaine on a second order fixed‐interval, fixed‐ratio schedule of i.v. drug injection or 3) self‐administer food on a comparable second order schedule of food delivery. In cocaine discrimination studies, CJB 090 did not substitute for cocaine, but significantly attenuated cocaine's discriminative stimulus effects when administered as a pretreatment. CJB 090 also significantly attenuated the partial cocaine‐like stimulus effects of the D3 receptor agonist PD128907, but enhanced the partial cocaine‐like stimulus effects of the D2 receptor agonist sumanirole. In self‐administration studies, CJB 090 did not attenuate responding maintained by i.v. injections of cocaine at a dose that reduced responding maintained by food. In a separate group of monkeys, observational tests revealed that CJB 090 did not induce scratching or biting (species‐typical effects of D2/3 receptor agonists) or catalepsy (typical effect of D2/3 receptor antagonists). The results provide little evidence that CJB 090 reduced cocaine's reinforcing effects. However they do suggest that CJB 090, acting primarily via a D3 receptor mechanism, antagonized the discriminative stimulus effects of cocaine at a dose that did not induce adverse observable effects.Supported by DA011054, NIDA‐IRP, RR00168. We thank J. Cao for CJB 090 synthesis.

Med Check

Med Check

Chronic treatment with aripiprazole induces differential gene expression in the rat frontal cortex

Chronic treatment of antipsychotic drugs can modulate gene expression in the brain, which may underscore their clinical efficacy. Aripiprazole is the first approved antipsychotic drug of the class of dopamine D2 receptor partial agonist, which has been shown to have similar efficacy and favourable side-effects profile compared to other antipsychotic drugs. This study aimed to identify differential gene expression induced by chronic treatment of aripiprazole. We used microarray-based gene expression profiling technology, real-time quantitative PCR and Western blot analysis to identify differentially expressed genes in the frontal cortex of rats under 4 wk treatment of aripiprazole (10 mg/kg). We were able to detect ten up-regulated genes, including early growth response gene 1, 2, 4 (Egr1, Egr2, Egr4), chromobox homolog 7 (Cbx7), cannabinoid receptor (Cnr1), catechol-O-methyltransferase (Comt), protein phosphatase 2c, magnesium dependent (Ppm2c), tachykinin receptor 3 (Tacr3), Wiscott-Aldrich syndrome-like gene (Wasl) and DNA methyltransferase 3a (Dnmt3a). Our data indicate that chronic administration of aripiprazole can induce differential expression of genes involved in transcriptional regulation and chromatin remodelling and genes implicated in the pathogenesis of psychosis.

Differences in agonist/antagonist properties at human dopamine D2 receptors between aripiprazole, bifeprunox and SDZ 208-912

Aripiprazole is the first dopamine D(2) receptor partial agonist approved for use in schizophrenia and bipolar disorder. Other partial agonists have failed in various stages of development, either for reasons of poor tolerability or lack of efficacy. We conducted an in vitro comparative analysis between aripiprazole, bifeprunox, SDZ 208-912, OPC-4392 and ACR16 in attempt to correlate specific pharmacological properties with clinical outcome. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of this inhibition produced by dopamine in clonal CHO cell lines expressing high and low densities of human dopamine D(2L) and D(2S) receptors. In cells expressing high receptor densities, all drugs except ACR16 predominantly behaved as agonists. However, in cells expressing low receptor densities, all drugs showed significantly lower maximal effects than dopamine. Aripiprazole's intrinsic activity was lower than that observed with bifeprunox and OPC-4392, and higher than that of SDZ 208-912. Aripiprazole's antagonist activity was greater than that of bifeprunox and OPC-4392, and less than that of SDZ 208-912. In conclusion, our data suggests that aripiprazole's unique intrinsic activity profile may account for its demonstrated clinical efficacy in the treatment of both positive and negative symptoms of schizophrenia, as well as its demonstrated low liability for parkinsonism and hyperprolactinemia. A higher degree of intrinsic activity, and lower relative antagonist activity, such as that observed with bifeprunox and OPC-4392 may translate into a clinically suboptimal improvement of positive symptoms. SDZ 208-912's intrinsic activity may be lower than the optimal level needed to minimize extrapyramidal symptoms.

Aripiprazole acts as a selective dopamine D2 receptor partial agonist

Aripiprazole has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D2 and 5-HT1A receptors and antagonism of the 5-HT2 receptor contribute to the clinical profile of aripiprazole, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of aripiprazole. This report reviews published and unpublished data that suggest that aripiprazole acts as a selective partial agonist at the dopamine D2 receptor and does not affect 5-HT receptors at therapeutic doses.

Aripiprazole as the Causative Agent of Neuroleptic Malignant Syndrome

Aripiprazole as the Causative Agent of Neuroleptic Malignant Syndrome

Effect of Aripiprazole, a Partial Dopamine D2 Receptor Agonist, on Increased Rate of Methamphetamine Self-Administration in Rats with Prolonged Session Duration

Aripiprazole is a dopamine (DA) D(2) receptor partial agonist, approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia. DA receptor partial agonists have been previously assessed as potential therapeutic agents for cocaine dependence. The present experiment examined the effect of aripiprazole on methamphetamine self-administration in a rodent model of an increasing drug self-administration with prolonged session duration. Wistar rats were allowed to self-administer methamphetamine (0.05 mg/kg/injection, intravenously) in either 1-h (short access: ShA rats) or 6-h sessions (long access: LgA rats). After 15 sessions, the dose-response function of methamphetamine was determined under either a progressive- or a fixed-ratio schedule. Next, the effect of aripiprazole (0.3-10 mg/kg, subcutaneuously (s.c.)) on the dose-response function was examined. LgA rats exhibited an increasing rate of methamphetamine self-administration. Responding for methamphetamine by LgA rats was higher than that of ShA rats under both schedules. Pretreatment with aripiprazole shifted the dose-response function of methamphetamine to the right in both LgA and ShA rats. However, the effect of aripiprazole was greater in LgA than ShA rats. In in vitro receptor binding assay, no change in the level of D(2) DA receptors in the nucleus accumbens and the striatum was found in any group. The present data suggest increased sensitivity of the dopaminergic system to aripiprazole in LgA rats compared with ShA rats. However, mechanisms other than downregulation of D(2) DA receptors in the nucleus accumbens and the striatum may be responsible for the increased sensitivity of the dopaminergic function in LgA rats.

Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT 1A Receptors

Most second-generation, atypical, dopamine (DA) D2/5-HT2 blocking antipsychotics still induce extrapyramidal side effects (EPS) in higher doses. Weight gain and metabolic disturbances are also a problem, and negative and cognitive symptoms have not been sufficiently addressed. The current brain DA mesolimbic hyperactive/mesocortical hypoactive hypothesis of schizophrenia suggests that DA D2/5-HT1A receptor partial agonist properties may be more efficacious with less side effects. DA D2 receptor partial agonists may stabilize a hyperactive/hypoactive DA condition. Additional 5-HT1A stimulation may enhance therapeutic efficacy and also improve EPS liability profile. In clinical trials in schizophrenic patients, the novel DA D2/5-HT1A partial agonist bifeprunox indeed demonstrates therapeutic efficacy, a safe EPS profile and appears beneficial regarding weight gain, prolactin, blood lipid and glucose levels and cardiac rhythm. The data on bifeprunox are promising and suggest that combined DA D2/5-HT1A partial agonism may well be important properties for future-generation antipsychotics.

In vitro functional characteristics of dopamine D2 receptor partial agonists in second and third messenger-based assays of cloned human dopamine D2Long receptor signalling

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): A novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.

Aripiprazole Augmentation of Antidepressants for the Treatment of Partially Responding and Nonresponding Patients With Major Depressive Disorder

To determine the efficacy and tolerability of aripiprazole, a dopamine D2 and 5-HT1A receptor partial agonist, as augmentation of antidepressant treatment of partially responding and nonresponding patients with major depressive disorder. Fifteen patients with major depressive disorder (diagnosed with a site-generated form described in the text) and an incomplete response or no response to > or = 8 weeks of antidepressant (selective serotonin reuptake inhibitor, venlafaxine, or bupropion) monotherapy were treated with aripiprazole augmentation in an 8-week, open-label study. Data were gathered from July 2003 to March 2004. The mean duration of antidepressant monotherapy at baseline was 43.1 weeks. At baseline, mean Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Depression (HAM-D) scores were 4.3 and 18.9, respectively. After initiation of aripiprazole augmentation, 6 of 15 patients achieved remission (HAM-D score < or = 7) at week 1, and 9 of 15 patients remitted by week 2. All 8 completers achieved remission by study endpoint. Akathisia in 2 patients who withdrew prematurely prompted a reduction in the starting dose of aripiprazole from 10 mg/day to 2.5 mg/day, resulting in a 50% reduction in attrition due to akathisia (2/7 withdrew due to akathisia with the 10-mg starting dose, 1/8 withdrew due to akathisia with the 2.5-mg starting dose). Discontinuation rates after 4 weeks of treatment were lower for the 2.5-mg starting dose (1/8 patients) than for the 10-mg starting dose (3/7 patients). Overall discontinuation rates at endpoint were lower for the 2.5-mg dose (3/8 patients) than the 10-mg dose (4/7 patients). Response to aripiprazole augmentation did not appear to be related to the antidepressant used at study initiation. Aripiprazole is an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder when administered in combination with standard antidepressant therapy. Based on this clinical signal, a double-blind, placebo-controlled trial is warranted.

Dopamine D3 Receptor Partial Agonists and Antagonists as Potential Drug Abuse Therapeutic Agents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic

Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((−)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated cAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia.

Dopamine D3 Receptor Partial Agonists and Antagonists as Potential Drug Abuse Therapeutic Agents

Dopamine D3 Receptor Partial Agonists and Antagonists as Potential Drug Abuse Therapeutic Agents

Aripiprazole, a novel antipsychotic agent: Dopamine D2 receptor partial agonist

It is obvious that DA is an important neurotransmitter in vivo. It is involved in a variety of physiological processes such as mental processes, motor function and hormone regulation. In this context, it is quite understandable that a DA D2 receptor antagonist that inhibits the DA D2 receptor regardless of the state of activity of dopaminergic neurotransmission and inhibit the physiological function of DA can have a variety of adverse effects. In contrast to DA D2 antagonists, aripiprazole acts as an antagonist at the DA D2 receptor in the state of excessive dopaminergic neurotransmission, while it acts as an agonist at the DA D2 receptor in the state of low dopaminergic neurotransmission, and thus attempts to bring the state of dopaminergic neurotransmission to normal. This activity of aripiprazole to regulate dopaminergic neurotransmission is physiologically reasonable, and can be regarded as a stabilizing effect, for which aripiprazole is called a dopamine system stabilizer.