D3 Receptor Ligands Research Articles

BOPPY-based novel fluorescent dopamine D2 and D3 receptor ligands

Dopamine is one of the crucial neurotransmitters in the human brain. Its out-of-range concentration can lead to various neurological diseases with special interest for dopamine D2 and D3 receptor subtypes. Although BODIPY is a highly versatile structural moiety for fluorescence labeling, we have looked out for structurally related pyridine-based moieties. We used BOPPY labelling of well-described D2R/D3R pharmacophores to obtain ligands with moderate to low nanomolar binding affinities as well as low to excellent quantum yields for bright fluorescence ligands. To best of our knowledge, this is the first report on the application of BOPPY fluorophores to GPCR ligands. This approach offers a general applicable way for fluorescence labelling via primary aliphatic amine elements.

Dopamine D2L receptor density influences the recruitment of β-arrestin2 and Gi1 induced by antiparkinsonian drugs

IntroductionBrain imaging studies have highlighted that the density of dopamine D2 receptors markedly fluctuates across the stages of Parkinson's disease and in response to pharmacological treatment. Moreover, receptor density constitutes a molecular determinant for the signaling profile of D2 receptor ligands. We therefore hypothesized that variations in receptor expression could influence D2 receptor response to antiparkinsonian drugs, most notably with respect to the recruitment bias between Gi1 and β-arrestin2. MethodsThe recruitment bias of dopamine, pramipexole, ropinirole, and rotigotine was examined using a nanoluciferase-based biosensor for probing the interactions of the D2L receptor with either Gi1 or β-arrestin2. The characterization of the functional selectivity of these D2 receptor agonists was performed at two distinct D2L receptor densities by taking advantage of a cell model carrying an inducible system that enables the overexpression of the D2L receptor when exposed to doxycycline. ResultsA high receptor density oriented the balanced signaling profile of dopamine towards a preferential recruitment of Gi1. It also moderated the marked Gi1 and β-arrestin2 biases of pramipexole and rotigotine, respectively. At variance, the Gi1 bias of ropinirole appeared as not being influenced by D2L receptor density. ConclusionsTaken together, these observations highlight receptor density as a key driver of the signaling transducer recruitment triggered by antiparkinsonian agents. Moreover, given the putative beneficial properties of β-arrestin2 in promoting locomotion, this study provides molecular insights that position the arrestin-biased ligand rotigotine as a putatively more beneficial D2 receptor agonist for the treatment of early and late Parkinson's disease.

Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D3 receptor ligands

Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D3 receptor ligands

Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of parkinson's disease

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Receptor density influences ligand-induced dopamine D2L receptor homodimerization

Chronic treatments with dopamine D2 receptor ligands induce fluctuations in D2 receptor density. Since D2 receptors tend to assemble as homodimers, we hypothesized that receptor density might influence constitutive and ligand-induced homodimerization. Using a nanoluciferase-based complementation assay to monitor dopamine D2L receptor homodimerization in a cellular model enabling the tetracycline-controlled expression of dopamine D2L receptors, we observed that increasing receptor density promoted constitutive dopamine D2L receptor homodimerization. Receptor full agonists promoted homodimerization, while antagonists and partial agonists disrupted dopamine D2L receptor homodimers. High receptor densities enhanced this inhibitory effect only for receptor antagonists. Taken together, our findings indicate that both receptor density and receptor ligands influence dopamine D2L receptor homodimerization, albeit excluding any strict correlation with ligands’ intrinsic activity and highlighting further complexity to dopaminergic pharmacology.

3D-ALMOND-QSAR Models to Predict the Antidepressant Effect of Some Natural Compounds.

The current treatment of depression involves antidepressant synthetic drugs that have a variety of side effects. In searching for alternatives, natural compounds could represent a solution, as many studies reported that such compounds modulate the nervous system and exhibit antidepressant effects. We used bioinformatics methods to predict the antidepressant effect of ten natural compounds with neuroleptic activity, reported in the literature. For all compounds we computed their drug-likeness, absorption, distribution, metabolism, excretion (ADME), and toxicity profiles. Their antidepressant and neuroleptic activities were predicted by 3D-ALMOND-QSAR models built by considering three important targets, namely serotonin transporter (SERT), 5-hydroxytryptamine receptor 1A (5-HT1A), and dopamine D2 receptor. For our QSAR models we have used the following molecular descriptors: hydrophobicity, electrostatic, and hydrogen bond donor/acceptor. Our results showed that all compounds present drug-likeness features as well as promising ADME features and no toxicity. Most compounds appear to modulate SERT, and fewer appear as ligands for 5-HT1A and D2 receptors. From our prediction, linalyl acetate appears as the only ligand for all three targets, neryl acetate appears as a ligand for SERT and D2 receptors, while 1,8-cineole appears as a ligand for 5-HT1A and D2 receptors.

Design, synthesis and preliminary bioactivity evaluation of bitopic benzopyranomorpholine analogues as selective dopamine D3 receptor ligands as anti-drug addiction therapeutic agents

Three series of bitopic benzopyranomorpholine analogues were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine D3 receptor. Binding affinities of target compounds were determined using the method of radioligand binding assay. Most compounds demonstrated considerable binding affinities and selectivity for D3 receptor. Besides, the compounds were screened for their ability to alleviate withdrawal symptoms of opioid addiction in animal behavioral models. The results showed that compound 20h displayed nanomolar affinity for the D3R, and exhibited anti-drug addiction efficacy in the animal model of of naloxone-induced withdrawal symptoms in morphine-dependent mice.

Convincing Catalytic Performance of Oxo-Tethered Ruthenium Complexes for Asymmetric Transfer Hydrogenation of Cyclic α-Halogenated Ketones through Dynamic Kinetic Resolution.

A highly efficient dynamic kinetic resolution of cyclic halohydrins was achieved by the asymmetric transfer hydrogenation of racemic α-haloketones. Bifunctional oxo-tethered Ru(II) catalysts could promote the reduction without deterioration of halogens. By structural tuning of the catalyst, chiral alcohols having halogen, ester, carboxamide, and sulfone functions were obtained variably with excellent diastereo- and enantioselectivities (up to >99:1 d.r. and >99.9 ee), which provided a concise synthetic approach to a dopamine D3 receptor ligand, (+)-PHNO.

Dual Role of the Rhodium(III) Catalyst in C-H Activation: [4 + 3] Annulation of Amide with Allylic Alcohols to 7-Membered Lactams.

[4 + 3] annulation of primary and secondary benzamide and cinnamamide derivatives using allyl alcohol as a coupling partner catalyzed by Rh(III) is reported, where Rh(III) is playing a dual role of an oxidant and a catalyst for C-H activation. The Rh-catalyst oxidizes allyl alcohol to its carbonyl derivative, and the in situ-generated carbonyl compound reacts with benzamide in the presence of the Rh-catalyst, forming the corresponding alkylated products. Mechanistic studies show that AgSbF6 is also playing a dual role. Apart from being a halide scavenger, AgSbF6 catalyzes the cyclization of the alkylated product, forming the desired lactam. The current method has good synthetic application and is useful for synthesizing a few biologically active compounds that can act as the dopamine D3 receptor ligand, including berberine-like analogues. The deuteration study and control experiments helped us to propose the mechanism.

Recent findings leading to the discovery of selective dopamine D4 receptor ligands for the treatment of widespread diseases.

Since its discovery, the dopamine D4 receptor (D4R) has been suggested to be an attractive target for the treatment of neuropsychiatric diseases. Novel findings have renewed the interest in such a receptor as an emerging target for the management of different diseases, including cancer, Parkinson's disease, alcohol or substance use disorders, eating disorders, erectile dysfunction and cognitive deficits. The recently resolved crystal structures of D4R in complexes with the potent ligands nemonapride and L-745870 strongly improved the knowledge on the molecular mechanisms involving the D4R functions and may help medicinal chemists in drug design. This review is focused on the recent development of the subtype selective D4R ligands belonging to classical or new chemotypes. Moreover, ligands showing functional selectivity toward G protein activation or β-arrestin recruitment and the effects of selective D4R ligands on the above-mentioned diseases are discussed.

D1 receptors in the anterior cingulate cortex modulate basal mechanical sensitivity threshold and glutamatergic synaptic transmission

The release of dopamine (DA) into target brain areas is considered an essential event for the modulation of many physiological effects. While the anterior cingulate cortex (ACC) has been implicated in pain related behavioral processes, DA modulation of synaptic transmission within the ACC and pain related phenotypes remains unclear. Here we characterized a Crispr/Cas9 mediated somatic knockout of the D1 receptor (D1R) in all neuronal subtypes of the ACC and find reduced mechanical thresholds, without affecting locomotion and anxiety. Further, the D1R high-efficacy agonist SKF 81297 and low efficacy agonist (±)-SKF-38393 inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) currents in the ACC. Paradoxically, the D1R antagonists SCH-23390 and SCH 33961 when co-applied with D1R agonists produced a robust short-term synergistic depression of AMPAR currents in the ACC, demonstrating an overall inhibitory role for D1R ligands. Overall, our data indicate that absence of D1Rs in the ACC enhanced peripheral sensitivity to mechanical stimuli and D1R activation decreased glutamatergic synaptic transmission in ACC neurons.

Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands.

2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (Ki = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.

Controlling receptor function from the extracellular vestibule of G-protein coupled receptors.

Receptor function is traditionally controlled from the orthosteric binding site of G-protein coupled receptors. Here, we show that the functional activity and signalling of human dopamine D2 and D3 receptor ligands can be fine-tuned from the extracellular secondary binding pocket (SBP) located far from the signalling interface suggesting optimization of the SBP binding part of bitopic ligands might be a useful strategy to develop GPCR ligands with designed functional and signalling profile.

Design and synthesis of bitopic 2-phenylcyclopropylmethylamine (pcpma) derivatives as selective dopamine d3 receptor ligands

Design and synthesis of bitopic 2-phenylcyclopropylmethylamine (pcpma) derivatives as selective dopamine d3 receptor ligands

Profiling of LINS01 compounds at human dopamine D2 and D3 receptors

Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, especially in the limbic areas, making them very attractive to designing drugs with synergistic and/or additive effects. The roles of these systems to treat schizophrenia, drug addiction, Parkinson’s and Alzheimer’s diseases, among others are widely known. The LINS01 compounds were previously reported as histamine H3 receptor (H3R) antagonists and some of them are under evaluation in rodent memory models. Considering their pharmacological potential and similarities to literature dopamine D2 receptor (D2R) and dopamine D3 receptor (D3R) ligands, this work aimed to evaluate these compounds as ligands these receptors by using [3H]spiperone displacement assays. A set of 11 compounds containing the dihydrobenzofuranyl-piperazine core with substituents at 5-position of dihydrobenzofuran ring and at the piperazine nitrogen was examined. The compounds showed low to moderate affinities at both, D2R and D3R. N-Phenyl compounds LINS01005 (1d), LINS01011 (1h), LINS01012 (1i) and LINS01016 (1k) showed the highest affinities in the set to D3R (Ki 0.3–1.5 µM), indicating that N-phenylpiperazine moiety increases the affinity to this receptor subtype with some selectivity, since they showed lower affinities to D2R (Ki 1.3–5.5 µM). With the LINS01 compounds showing moderate binding affinity, new lead structures for optimization with regards to combined H3R and D2R/D3R-ligands are provided. Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, and thus LINS01 compounds previously reported as histamine H3 receptor antagonists were evaluated as dopamine D2R and D3R ligands. The compounds showed micromolar affinities to both receptors

The effects of dopamine D4 receptor ligands on operant alcohol self-administration and cue- and stress-induced reinstatement in rats

Dopamine, a neurotransmitter with 5 receptor subtypes, is critical to the dependence-forming properties of drugs of abuse. The role of the dopamine D4 receptor subtype in substance use disorders has remained somewhat elusive but the recent development of selective ligands holds promise for future investigations of this receptor subtype in substance use disorders, including alcohol use disorder. The purpose of the present study was to further elucidate the effects of a selective antagonist (L-745,870) and agonist (PD 168,077) on alcohol self-administration and reinstatement induced either by cues or stress. It was found that the D4 antagonist, but not agonist, reduced alcohol intake at the highest doses. Further, the D4 antagonist reduced stress-induced reinstatement, with no effects on cue-induced reinstatement; the agonist was without effect on either form of reinstatement. The dopamine D4 receptor antagonist was without effect on food reinforcement. This work deepens existing lines of evidence that the dopamine D4 receptor is involved in substance use disorders and suggests that dopamine D4 receptor blockade diminishes motivation for alcohol-taking without influencing natural food rewards. Furthermore, there appears to be a plausible effect of dopamine D4 receptor blockade interfering with stress- but not cue-induced alcohol-seeking.

Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands.

As part of our on-going effort to explore the role of dopamine receptors in drug addiction and identify potential novel therapies for this condition, we have a identified a series of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide D3 ligands. Members of this class are highly selective for D3 versus D2, and we have identified two compounds (13g and 13r) whose rat in vivo IV pharmacokinetic properties that indicate that they are suitable for assessment in in vivo efficacy models of substance use disorders.

Evaluation of Functional Selectivity of Haloperidol, Clozapine, and LASSBio-579, an Experimental Compound With Antipsychotic-Like Actions in Rodents, at G Protein and Arrestin Signaling Downstream of the Dopamine D2 Receptor.

LASSBio-579, an N-phenylpiperazine antipsychotic lead compound, has been previously reported as a D2 receptor (D2R) ligand with antipsychotic-like activities in rodent models of schizophrenia. In order to better understand the molecular mechanism of action of LASSBio-579 and of its main metabolite, LQFM 037, we decided to address the hypothesis of functional selectivity at the D2R. HEK-293T cells transiently coexpressing the human long isoform of D2 receptor (D2LR) and bioluminescence resonance energy transfer (BRET)-based biosensors were used. The antagonist activity was evaluated using different concentrations of the compounds in the presence of a submaximal concentration of dopamine (DA), after 5 and 20 min. For both signaling pathways, haloperidol, clozapine, and our compounds act as DA antagonists in a concentration-dependent manner, with haloperidol being by far the most potent, consistent with its nanomolar D2R affinity measured in binding assays. In our experimental conditions, only haloperidol presented a robust functional selectivity, being four- to fivefold more efficient for inhibiting translocation of β-arrestin-2 (β-arr2) than for antagonizing Gi activation. Present data are the first report on the effects of LASSBio-579 and LQFM 037 on the β-arr2 signaling pathway and further illustrate that the functional activity could vary depending on the assay conditions and approaches used.

Using LeDock as a docking tool for computational drug design

Computer-aided drug design (CADD) is an emerging tool for research and drug development process as it reduces the time taken for the process of drug development and expense. Molecular docking technology, as one of the main method, has been widely used in many fields of drug development. Based on the dopamine D3 receptor target, this paper describes the method of molecular docking using LeDock software (Windows version) in combination with the docking process of eticlopride ligand and D3 receptor. This method can predict the binding mode of ligands to proteins, including binding energy, binding sites and attractive interactions types. Four representative D3 receptor ligands, including BP897, NGB2904, FAUC365 and SB277011A, were respectively docked with D3 receptor by this method. By analyzing the docking results, we can conclude that the molecular docking method using LeDock software plays an important role in the drug design process.

Rhesus Macaque Brain Atlas Regions Aligned to an MRI Template.

To aid in the analysis of rhesus macaque brain images, we aligned digitized anatomical regions from the widely used atlas of Paxinos et al. to a published magnetic resonance imaging (MRI) template based on a large number of subjects. Digitally labelled atlas images were aligned to the template in 2D and then in 3D. The resulting grey matter regions appear qualitatively to be well registered to the template. To quantitatively validate the procedure, MR brain images of 20 rhesus macaques were aligned to the template along with regions drawn by hand in striatal and cortical areas in each subject's MRI. There was good geometric overlap between the hand drawn regions and the template regions. Positron emission tomography (PET) images of the same subjects showing uptake of a dopamine D2 receptor ligand were aligned to the template space, and good agreement was found between tracer binding measures calculated using the hand drawn and template regions. In conclusion, an anatomically defined set of rhesus macaque brain regions has been aligned to an MRI template and has been validated for analysis of PET imaging in a subset of striatal and cortical areas. The entire set of over 200 regions is publicly available at https://www.nitrc.org/ . Graphical Abstract ᅟ.