Selective D2 Research Articles

Identification of a new selective dopamine D4 receptor ligand

The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4=0.84nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4=3.9nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100nM (Ki <100nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.

Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats

The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Alterations in glutamatergic and GABAergic signaling were recently demonstrated in the NAcc of rats after chronic intermittent ethanol (CIE) treatment, a model of alcohol dependence. Here we studied dopamine (DA) modulation of GABAergic signaling and how this modulation might be altered by CIE treatment. We show that the tonic current (I(tonic)) mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc core is differentially modulated by DA at concentrations in the range of those measured in vivo (0.01-1 μM), without affecting the postsynaptic kinetics of miniature inhibitory postsynaptic currents (mIPSCs). Use of selective D1 receptor (D1R) and D2 receptor (D2R) ligands revealed that I(tonic) potentiation by DA (10 nM) is mediated by D1Rs while I(tonic) depression by DA (0.03-1 μM) is mediated by D2Rs in the same MSNs. Addition of guanosine 5'-O-(2-thiodiphosphate) (GDPβS) to the recording pipettes eliminated I(tonic) decrease by the selective D2R agonist quinpirole (5 nM), leaving intact the quinpirole effect on mIPSC frequency. Recordings from CIE and vehicle control (CIV) MSNs during application of D1R agonist (SKF 38393, 100 nM) or D2R agonist (quinpirole, 2 nM) revealed that SKF 38393 potentiated I(tonic) to the same extent, while quinpirole reduced I(tonic) to a similar extent, in both groups of rats. Our data suggest that the selective modulatory effects of DA on I(tonic) are unaltered by CIE treatment and withdrawal.

The novel dopamine D3 receptor antagonist, SR 21502, reduces cocaine conditioned place preference in rats

Research has shown that dopamine (DA) D3 receptors play a crucial role in cocaine addiction. Recently, there has been a strong focus on the development of DA D3 receptor antagonists as potential pharmacological treatments for cocaine addiction. We investigated the ability of a novel selective D3 receptor antagonist SR 21502 to block the expression of cocaine-induced conditioned place preference (CPP) in rats. CPP was determined using a two-chamber apparatus. All of the animals had free access to both chambers on day 1, followed by 4 alternating conditioning days of cocaine injection (paired chamber) and 4 alternating non-conditioning days with saline (non-paired chamber). On the test day, animals were systemically treated with 0, 3.75, 7.5 or 15mg/kg of SR 21502, 10min prior to being placed in the CPP apparatus, and the time spent in each chamber was recorded for 15min. The amount of time spent in the cocaine-paired chamber on the test and pre-exposure days was analyzed. Vehicle-treated animals spent significantly more time in the cocaine-paired side during the test than during the pre-exposure session, indicating a cocaine CPP. SR 21502 produced a dose-related significant reduction in the time spent in the cocaine-paired side compared to vehicle. The DA D3 receptor antagonist SR 21502 blocks the rat's preference for the cocaine-paired chamber, thereby attenuating the rewarding effect of the cocaine cues. This suggests that this compound may be an effective pharmacological treatment against cocaine addiction.

Effects of selective dopamine D3 receptor compounds in nonhuman primate models of cocaine and methamphetamine abuse (661.8)

Within the dopaminergic system, the D3R has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. The present studies examined the effects of D3‐selective partial agonists and D3/D2R antagonists in three models of cocaine and MA abuse in rhesus monkeys. The highly selective D3 partial agonist PG619 and the D3/D2R antagonists buspirone and eticlopride were administered chronically to monkeys self‐administering cocaine and MA (n=3/group) under a food‐drug choice procedure in which complete cocaine and MA dose‐response curves were determined each session. Neither PG 619 (0.1‐3.0 mg/kg, i.v.), buspirone (0.01‐0.3 mg/kg, i.m.) nor eticlopride (0.001‐0.01 mg/kg, i.v.) significantly decreased cocaine or MA choice and intake while buspirone significantly increased the choice of low drug doses. The ability of buspirone to block reinstatement was also examined. Using the choice procedure in which saline was substituted for the self‐administered drug, buspirone (1.0‐1.7 mg/kg, p.o.) was found to block both cocaine‐ and MA‐induced reinstatement. In relation to this, buspirone (0.03‐0.3 mg/kg, i.m.) was also found to be effective in blocking cocaine and MA discrimination in a separate group of monkeys (n=3/group). Overall, these data indicate that while buspirone did not block the reinforcing effects of stimulants when studied under a food‐drug choice paradigm, it was effective in reducing reinstatement and in attenuating the discriminative stimulus effects of cocaine and MA, supporting a potential use for this compound in drug abuse treatment. DA012460Grant Funding Source: Supported by DA012460

Brain dopamine and individual differences in a behavioural measure of reward responsiveness: A pharmacogenetic study

Trait reward responsiveness has been theoretically linked to individual differences in the brain’s dopaminergic reward circuitry. Here, we investigated the effect of dopaminergic genes and a pharmacological modulation of dopamine activity on a laboratory-based measure of reward responsiveness. After receiving either placebo or the selective dopamine D2 receptor blocker sulpiride (200 mg, double-blind administration) 201 male students completed a probabilistic reward task in which two correct responses were differentially reinforced. As expected, the bias for the more frequently reinforced response increased across the three task blocks. In addition, the magnitude of this increase depended on participants’ catechol- O -methyltransferase (COMT) Val158Met genotype: Homozygous individuals (Val/Val and Met/Met carriers) showed stronger increases in response bias than heterozygous individuals (Val/Met carriers) and were, thus, more responsive to the reward contingencies. However, no significant effects of sulpiride on reward bias were observed. The results provide mixed support for dopamine theories of trait reward responsiveness.

Nonlinear Dose-Dependent Impact of D1 Receptor Activation on Motor Cortex Plasticity in Humans

The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosage-dependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans, we combined sulpiride, a selective D2 receptor antagonist, with the dopamine precursor l-DOPA (25, 100, and 200 mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared with the impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) at the primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose-response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex.

A D1 Receptor Antagonist, Ecopipam, for Treatment of Tics in Tourette Syndrome

Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and tic-reducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS. This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1-2) and then 100 mg daily (weeks 3-8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored. Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18-63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was -0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted.

Modulation Of Stem And Progenitor Cells, And Bleomycin-induced Pulmonary Fibrosis By Spiperone In Mice

Bleomycin-induced lung inflammation and fibrosis were assessed in a model of idiopathic pulmonary fibrosis in C57BL/6 mice and effect of spiperone on histopathological lung indicators, hematopoietic (HSC) and mesenchymal (MSC) stem cells and progenitor cells was characterized. Spiperone is a selective antagonist of D2 dopamine receptors which disturbs dopamine mediation. Hematoxylin and eosin staining showed spiperone decreased alveolar epithelial edema, exudation and infiltration of the alveoli walls and lumen by inflammatory cells (neutrophils, macrophages, plasma cells) after bleomycin instillation. Picrofuchsin staining by Van Gieson revealed spiperone decreases the area of connective tissue in the lung fibrotic phase of pulmonary fibrosis. ELISA assay determined the decrease levels of collagen type I, hydroxyproline and total collagen in lung homogenate after spiperone treatment. Number of “long-term” HSCs (Lin- Sca-1+c-Kit+CD34-), «short-term” HSCs (Lin-Sca-1+c-Kit+CD34+), hematopoietic progenitor cells and MSC-like cells in lung with pneumofibrosis decreased after spiperone treatment. This spiperone effect we connect to the violation of immature bone marrow cells migration. Additionally, spiperone inhibited clonal activity of hematopoietic (CFU-GEMM, CFU-G) and mesenchymal (CFU-F) progenitor of bone marrow, blood and lungs. An additional feature of the spiperone action was the ability to decrease the capacity of self-renewal and MSCs differentiation activity into adipocytes, osteoblasts, chondrocytes and fibroblast cells. Thus, a selective antagonist D2 of dopamine receptors spiperone can act as a potential antifibrotic agent for the treatment of toxic pulmonary fibrosis. The overall conclusion was that the neurotropic agent spiperone is able to influence the stem and progenitor cells in lung pathology effectively.

Montelukast: much more than an antiasthma drug

Montelukast (MK), a selective leukotriene D4 receptor antagonist, is used mainly to reduce eosinophilic inflammation in asthmatic patients. The primary objective of this mini-review is to describe novel additional targets for MK besides the lung and to highlight its antioxidant potential. Literature published between 2002 and 2013 was reviewed for significant antioxidant and anti-inflammatory properties of MK in various experimental models of inflammation rather than that in the airways of asthmatics. Evidence suggests the potential use of MK in many inflammatory diseases rather than asthma therapy.

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

Dopamine modulates frontomedial failure processing of agentic introverts versus extraverts in incentive contexts

The agency facet of extraversion (aE) describes individual differences in goal-directed behavior and has been linked to dopamine function in incentive contexts. Because dopamine presumably modulates the processing of negative feedback/failure, aE may relate to failure processing in incentive contexts. To test this hypothesis, N = 86 participants performed a virtual ball-catching task. An incentive context was created by displaying potential rewards and subtle manipulations of task performance, which either was (control group) or was not (incentive context group) made explicit. To probe the involvement of dopamine, participants received either placebo or the selective dopamine D2 receptor antagonist sulpiride (200mg). Failure processing was assessed through negative-feedback-evoked differences in the frontal midline theta electroencephalogram power (DFMT) and in the feedback-related negativity event-related potential component (FRN). Before incentives were introduced, DFMT (but not the FRN) was related to neuroticism/anxiety. Importantly, once incentives were displayed, aE was associated with DFMT, FRN, task performance, and changes in self-reported positive affect, which further depended on incentive context group and/or substance group: In the incentive context group but not in the control group, agentic extraverts showed relatively blunted DFMT after placebo. Sulpiride significantly enhanced DFMT, whereas it reduced FRN amplitudes and performance in agentic extra- versus introverts. These findings provide strong support for current dopamine models of aE and failure processing, and also highlight the importance of task context. Moreover, the dissociations of FRN and DFMT suggest the existence of two nonredundant electrophysiological indices of feedback processing, both relating to dopamine and aE.

D1 receptor agonist improves sleep–wake parameters in experimental parkinsonism

Both excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque monkey. Continuous sleep and wake electroencephalographic monitoring revealed no effect of the selective dopamine D2 receptor agonist quinpirole on EDS, whereas the selective dopamine D1 receptor agonist SKF38393 efficiently alleviated EDS and restored REM sleep to baseline values. The present results question the relevance of abandoning D1 receptor agonist treatment in PD as it might actually improve sleep-related disorders.

A Selective Role for Dopamine D4 Receptors in Modulating Reward Expectancy in a Rodent Slot Machine Task

Cognitive distortions regarding gambling outcomes confer vulnerability to pathological gambling. Using a rat slot machine task (rSMT), we previously demonstrated that the nonspecific D₂ agonist quinpirole enhances erroneous expectations of reward on near-miss trials, suggesting a pivotal role for the D₂ receptor family in mediating the near-miss effect. Identifying which receptor subtype is involved could facilitate treatment development for compulsive slot machine play. Thirty-two male Long Evans rats learned the rSMT. Three flashing lights could be set to on or off. A win was signaled if all three lights were set to on, whereas any other light pattern indicated a loss. Rats then chose between responding on the collect lever, which delivered 10 sugar pellets on win trials but a 10-second time penalty on loss trials, or to start a new trial instead. Performance was assessed following systemic administration of selective D₂, D₃, and D₄ receptor ligands. The selective D₂ antagonist L-741,626, the D₃ antagonist SB-277011-A, and the D₃ agonist PD128,907 had no effect. In contrast, the selective D₄ agonist PD168077 partially mimicked quinpirole's effects, increasing erroneous collect responses on nonwin trials, whereas the D₄ antagonist L-745,870 improved the error rate. L-745,870 was also the only antagonist that could attenuate the deleterious effects of quinpirole. The dopamine D₄ receptor is critically involved in signaling reward expectancy in the rSMT. The ability of L-745,870 to reduce the classification of losses as wins suggests that D₄ antagonists could be effective in treating problematic slot machine play.

Effects of chronic injections of clebopride in low doses on behavior reactions of white rats

Effects of the selective D2 receptors antagonist clebopride on behavior of adult male rats was studied in such tests as sucrose consumption, open field, elevated plus maze, and complex maze with food reinforcement. The drug was injected in small doses (0.2 and 0.4 mg/kg) chronically within two weeks. It was shown that clebopride may have an influence on emotional and motivational state of experimental animals, on the one hand, causing depressive-like changes, and on the other hand, improving learning ability and exploratory reactions. A variety of consequences of D2 antagonist action is caused, apparently, by a competition of its post- and presynaptic effects.

P.1.j.022 A dopamine D1 agonist improved ketamineinduced spatial working memory dysfunction in common marmosets

Using the RNA arbitrarily-primed PCR and the competitive RT-PCR, we have isolated the neocortical transcripts that are upregulated and unchanged in the adult and infant rats, respectively, after a systemic injection of an N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP), and found them identical to the synapse-associated protein-97 (SAP97) gene mRNAs. The upregulation of the SAP97 transcripts in the adult neocortex after the acute PCP injection was mimicked by another NMDA antagonist, dizocilpine, but not by the indirect dopamine agonists, methamphetamine and cocaine, a selective D1 receptor antagonist SCH23390, a D2 receptor-preferring antagonist haloperidol and a GABAergic anesthetic pentobarbital. Moreover, the pretreatment with a typical antipsychotic haloperidol failed to antagonize the increased neocortical SAP97 gene expression by PCP. These findings suggest that SAP97 might be involved in the molecular basis of the development-dependent onset of the non-dopaminergic symptoms seen in schizophrenia and the schizophrenia-like psychosis induced by NMDA receptor blocking.

P.1.h.015 Differential effect of c-Fos activation associated with JNJ16259685 after an agonistic encounter as compared with grouped mice

The atypical neuroleptic, sulpiride is a selective D2 antagonist, having a preferential action on mesolimbic regions. The effects of acute and chronic treatment with sulpiride on aggressive behaviour in male mice were studied using an ethologically based analysis. It was hypothesized that sulpiride would diminish “threat” and “attack” but would not produce marked “immobility”, because of the mesolimbic effect referred to above. Isolated albino male mice (experimental animals) were confronted by “standard opponents”. Acutely-treated experimental animals received an intraperitoneal injection of sulpiride (20, 50 or 100 mg/kg) 30 min before testing. Chronically-treated animals received sulpiride (10, 20 or 50 mg/kg) once a day for 7 or 14 consecutive days. Acute treatment with sulpiride had an obvious antiaggressive effect, with significantly decreased time devoted to “attack” and “threat” behaviour. Although time spent in “immobility” was modestly increased, the time devoted to other motor behaviour was also increased. Chronic treatment for 1 or 2 weeks did not change any behavioural category, except “immobility”. The antiaggressive action of acutely administered sulpiride is interpreted as a relatively specific dopaminergic antagonist effect and not as merely a non-specific correlate of its disruptive action on motor behaviour. The possible anxiolytic action of sulpiride is also discussed.

Click chemistry based synthesis of dopamine D4 selective receptor ligands for the selection of potential PET tracers

Taking advantage of click chemistry, a library of N-arylpiperazinylmethyl triazoles bearing fluoro substituted appendages was synthesized and the target compounds were investigated for dopamine and serotonin receptor binding. With the aim to bias their hydrophilicity and to optimize their D4 receptor affinity and selectivity, a concise series of triazoles containing fluoroalkyl, fluoroalkoxy, fluoroalkoxyphenyl, and deoxyfluoroglucosyl substituents was studied. The D4 receptor affinity and selectivity could be tuned by altering the chemical moiety attached to the triazole unit. Among the test compounds, the fluoroethoxyphenyl derivative 15b showed weak partial agonism at D4 and a Ki value of 14nM, while its fluoropropoxyphenyl homologue 16a turned out to act as a neutral D4 antagonist (Ki=5.1nM). Both, 15b and 16a revealed an excellent balance between D4 receptor affinity and subtype selectivity, providing lead candidates for the development of 18F-labeled radioligands for D4 receptor imaging studies by positron emission tomography (PET).

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments. We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats. In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10mg/kg, IP)-induced locomotor activity, respectively. SR 21502 produced significant, dose-related (3.75, 7.5 and 15mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity. SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine's rewarding, incentive motivational and stimulant effects.

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

In this article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA- and MPP+-induced toxicity in a dose-dependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinson's disease.

2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure–activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.