RESUMEN
Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD3R:GαOßγ complex bound to the D3R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.
Asunto(s)
Microscopía por Crioelectrón , Receptores de Dopamina D3 , Humanos , Sitios de Unión , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D3/química , Receptores de Dopamina D3/agonistas , Células HEK293 , Ligandos , Unión Proteica , Animales , Modelos MolecularesRESUMEN
In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.
Asunto(s)
Toma de Decisiones , Modelos Animales de Enfermedad , Globo Pálido , Enfermedad de Parkinson , Pramipexol , Receptores de Dopamina D3 , Animales , Pramipexol/farmacología , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Toma de Decisiones/efectos de los fármacos , Globo Pálido/metabolismo , Globo Pálido/efectos de los fármacos , Masculino , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D3/agonistas , Agonistas de Dopamina/farmacología , Benzotiazoles/farmacología , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.
Asunto(s)
Agonistas de Dopamina , Dopamina , Pramipexol , Receptores de Dopamina D2 , Receptores de Dopamina D3 , Pramipexol/farmacología , Animales , Humanos , Agonistas de Dopamina/farmacología , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Dopamina/metabolismo , Benzotiazoles/farmacología , Locomoción/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Nivel de Alerta/efectos de los fármacosRESUMEN
Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors, including D2 (D2R) and D3 (D3R) receptors, remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analog of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.
Asunto(s)
Bromocriptina , Agonistas de Dopamina , Receptores de Dopamina D2 , Transducción de Señal , Animales , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/agonistas , Bromocriptina/farmacología , Bromocriptina/uso terapéutico , Ratones , Transducción de Señal/efectos de los fármacos , Masculino , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Ratones Endogámicos C57BL , Resistencia a la Insulina/fisiología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Humanos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D3/agonistasRESUMEN
Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the present study, we investigated the role of the dopamine D3 receptor in the thalamic mediodorsal (MD) and ventromedial (VM) nuclei mediated descending control of nociception and intramuscular (i.m.) 2.5% formalin-induced persistent muscle nociception. Paw withdrawal reflexes were measured in naive rats and rats subjected to PD induced by unilateral microinjection of 6 µg 6-OHDA into the rat striatum. Formalin-induced muscle nociception in phase 1, inter-phase, and phase 2 was significantly greater in PD rats compared to naive and vehicle-treated rats (P < 0.001). PD rats exhibited bilaterally mechanical hyperalgesia and heat hypoalgesia in formalin-induced muscle nociception. Microinjection of SK609, a dopamine D3 receptor agonist, at various doses (2.5-7.5 nmol/0.5 µl) into the thalamic VM nucleus dose-dependently prolonged heat-evoked paw withdrawal latencies in both naive and PD rats. Administration of SK609 to either the MD or VM nuclei had no effect on noxious mechanically evoked paw withdrawal reflexes. Pre-treatment of the thalamic MD nucleus with SK609 significantly attenuated formalin-induced nociception, and reversed mechanical hyperalgesia, but not heat hypoalgesia. Pre-treatment of the thalamic VM nucleus with SK609 inhibited formalin-induced nociception in the late phase of phase 2 (30-75 min) and heat hypoalgesia, but not mechanical hyperalgesia (P < 0.05). It is suggested that the dopamine D3 receptors in the thalamus play an antinociceptive role in the descending modulation of nociception. Activation of D3 receptors within the thalamic MD and VM nuclei attenuates descending facilitation and enhances descending inhibition in rats during PD.
Asunto(s)
Modelos Animales de Enfermedad , Formaldehído , Nocicepción , Ratas Sprague-Dawley , Receptores de Dopamina D3 , Animales , Ratas , Masculino , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/metabolismo , Formaldehído/toxicidad , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Tálamo/efectos de los fármacos , Tálamo/metabolismo , Dimensión del Dolor/métodos , Oxidopamina/toxicidadRESUMEN
Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the α4ß2 nicotinic acetylcholine receptor, the D3R-nAChR heteromer, activated by both nicotine and dopamine D2 and D3 receptors agonists, such as quinpirole, and crucial for dopaminergic neuron homeostasis. We now report that D3R-nAChR heteromer activity is potentiated by 17-ß-estradiol which acts as a positive allosteric modulator by binding a specific domain on the α4 subunit of the nicotinic receptor protomer. In mouse dopaminergic neurons, in fact, 17-ß-estradiol significantly increased the ability of nicotine and quinpirole in promoting neuron dendritic remodeling and in protecting neurons against the accumulation of α-synuclein induced by deprivation of glucose, with a mechanism that does not involve the classical estrogen receptors. The potentiation induced by 17-ß-estradiol required the D3R-nAChR heteromer since either nicotinic receptor or dopamine D3 receptor antagonists and interfering TAT-peptides, but not the estrogen receptor antagonist fulvestrant, specifically prevented 17-ß-estradiol effects. Evidence of estrogens neuroprotection, mainly mediated by genomic mechanisms, have been provided, which is in line with epidemiological data reporting that females are less likely to develop Parkinson's Disease than males. Therefore, potentiation of D3R-nAChR heteromer activity may represent a further mechanism by which 17-ß-estradiol reduces dopaminergic neuron vulnerability.
Asunto(s)
Neuronas Dopaminérgicas , Estradiol , Fármacos Neuroprotectores , Receptores de Dopamina D3 , Receptores Nicotínicos , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D3/agonistas , Estradiol/farmacología , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Receptores Nicotínicos/metabolismo , Ratones , Fármacos Neuroprotectores/farmacología , Femenino , MasculinoRESUMEN
BACKGROUND: JX11502MA is a potent partial agonist of dopamine D2 and D3 receptors, with a preferential binding profile for D3 receptors in vitro, potentially for treating schizophrenia. METHODS: A first-in-human, randomized, double-blind, placebo-controlled, single ascending dose clinical trial was designed. The subjects were randomly assigned to receive JX11502MA and placebo capsules with seven ascending dose groups: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 6 mg, and 8 mg. The PK profiles of JX11502MA and its metabolites were evaluated, along with a safety and tolerability assessment. RESULTS: Considering the safety of participants, the dose escalation was halted at 3 mg. Following single-dose administration, JX11502MA exhibited rapid absorption with a median Tmax ranging from 1 to 1.75 h. The terminal half-life of JX11502MA ranged from 73.62 to 276.85 h. The most common treatment-emergent adverse events (TEAEs) for subjects receiving JX11502MA were somnolence (56.3%), dizziness (18.8%), nausea (21.9%), vomiting (18.8%), and hiccups (18.8%). CONCLUSIONS: JX11502MA was generally well tolerated at a single dose of 0.25 to 3 mg. The PK profiles and safety characteristics in this study indicated that JX11502MA has the potential to be a favorable treatment option for patients with schizophrenia. TRIAL REGISTRATION: https://clinicaltrials.gov (identifier: NCT05233657).
Asunto(s)
Receptores de Dopamina D2 , Receptores de Dopamina D3 , Humanos , Área Bajo la Curva , China , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Pueblos del Este de Asia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistasRESUMEN
INTRODUCTION: Comorbidity of substance use disorder (SUD) with schizophrenia, referred to as dual disorder (DD), significantly increases morbidity and mortality compared to schizophrenia alone. A dopaminergic dysregulation seems to be a common pathophysiological basis of the comorbidity. AREAS COVERED: This article reports the current evidence on the role of dopamine dysregulations in DD, the pharmacological profile of cariprazine, a partial agonist of D3 and D2 dopamine receptors, and first clinical observations that may support its usefulness in the therapy of DD. PubMed/MEDLINE was searched for the keywords 'cariprazine,' 'schizophrenia,' 'dual disorder,' 'dopamine,' and 'dopamine receptor.' Preclinical and clinical studies, and reviews published in English were retrieved. EXPERT OPINION: Although the management of DD remains challenging, and the evidence for pharmacologic treatments is still unsatisfactory, cariprazine may be a candidate medication in DD due to its unique mechanism of action. Preliminary clinical experiences suggest that cariprazine has both antipsychotic and anticraving properties and should be considered early in patients with DD.
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Esquizofrenia , Trastornos Relacionados con Sustancias , Humanos , Esquizofrenia/tratamiento farmacológico , Dopamina/uso terapéutico , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/uso terapéutico , Receptores de Dopamina D2/agonistas , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/tratamiento farmacológicoRESUMEN
A new generation of dual-target µ opioid receptor (MOR) agonist/dopamine D3 receptor (D3R) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and D3R, respectively, improving the dopamine receptor subtype selectivity (e.g., D3R over D2R) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted trans-(2S,4R)-pyrrolidine and trans-phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists TRV130 (3) or loperamide (6). The lead compounds 46, 84, 114, and 121 have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via D3R antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.
Asunto(s)
Analgésicos Opioides , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/farmacología , Analgésicos Opioides/química , Dopamina , Ligandos , Analgésicos/farmacología , Receptores de Dopamina D3/agonistas , Receptores Opioides mu/agonistasRESUMEN
Over three decades of evidence indicate that dopamine (DA) D3 receptors (D3R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective D3R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D3R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D3R system. Third, the synthesis and characterization of highly potent and selective D3R antagonists/partial agonists have further strengthened the role of the D3R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D3R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D3R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D3R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.
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Estimulantes del Sistema Nervioso Central , Trastornos Relacionados con Sustancias , Humanos , Analgésicos Opioides/uso terapéutico , Dopamina , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/uso terapéutico , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/uso terapéutico , Estimulantes del Sistema Nervioso Central/farmacología , Trastornos Relacionados con Sustancias/tratamiento farmacológicoRESUMEN
The dopamine D3 receptor (D3R) plays a prominent role in the modulation of cognition in healthy individuals, as well as in the pathophysiological mechanism underlying the cognitive deficits affecting patients suffering from neuropsychiatric disorders. At a therapeutic level, a growing body of evidence suggests that the D3R blockade enhances cognitive and thus it may be an optimal therapeutic strategy against cognitive dysfunctions. However, this is not always the case because other ligands targeting the D3R, and behaving as partial agonists or biased agonists, may exert their pro-cognitive effect by maintaining adequate level of dopamine in key brain areas tuning cognitive performances. In this chapter, we review and discuss preclinical and clinical findings with the aim to remark the crucial role of the D3R in cognition and to strengthen the message that drugs targeting D3R may be excellent cognitive enhancers for the treatment of several neuropsychiatric and neurological disorders.
Asunto(s)
Disfunción Cognitiva , Receptores de Dopamina D3 , Humanos , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Dopamina , Cognición , Encéfalo/metabolismoRESUMEN
Restless Legs Syndrome (RLS) is a sensorimotor disorder that severely affects sleep. It is characterized by an urge to move the legs that is often accompanied by periodic limb movements during sleep (PLMS). RLS has a high prevalence in the population and is usually a life-long condition. While its origins remain unclear, RLS is initially highly responsive to treatment with dopaminergics that target the D3 receptor. However, over time patients often develop a gradual tolerance that can lead to the emergence of adverse effects and the augmentation of the symptoms. While the basal ganglia and the striatum control leg movements, the lumbar spinal cord is the gateway for the sensory processing of the symptoms and critical for the associated leg movements. D3 receptors are highly expressed in nucleus accumbens (NAc) of the striatum and the sensory-processing areas of the spinal dorsal horn. In contrast, D1 receptors are strongly expressed throughout the entire striatum and in the ventral horn of the spinal cord. Long-term treatment with D3 receptor full agonists is associated with an upregulation of the D1 receptor subtype, and D3 and D1 receptors can form functional heteromers, in which the D3R controls the D1R function. It is conceivable that the switch from beneficial treatment to augmentation observed in RLS patients after prolonged D3R agonist exposure may be the result of unmasked D1-like receptor actions.
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Síndrome de las Piernas Inquietas , Humanos , Síndrome de las Piernas Inquietas/tratamiento farmacológico , Síndrome de las Piernas Inquietas/diagnóstico , Receptores de Dopamina D3/agonistas , Agonistas de Dopamina , Médula EspinalRESUMEN
To follow up on our previous report on bivalent compounds exhibiting potent co-operative binding at dopamine D2 receptors, we modified the structure of the linker in our earlier bivalent molecules (S)-6-((9-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)nonyl)-(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ia) and (S)-6-((10-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)decyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ib) (Fig. 1) connecting the two pharmaophoric moieties to observe any tolerance in maintaining similar affinities and potencies. Specifically, we introduced aromatic and piperazine moieties in the linker to explore their effect. Overall, similar activities at D2 receptors as observed in our earlier study was maintained in the new molecules e.g. (6S,6'S)-6,6'-((1,4-phenylenebis(ethane-2,1-diyl))bis(propylazanediyl))bis(5,6,7,8-tetrahydronaphthalen-1-ol) (D-382) (Ki, D2 = 3.88 nM). The aromatic moiety in D-382 was next functionalized by introducing hydroxyl groups to mimic polyhydroxy natural products which are known to interact with amyloidogenic proteins. Such a transformation resulted in development of compounds like 2,5-bis(2-(((S)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)benzene-1,4-diol (D-666) (Ki, D2 = 7.62 nM) which retained similar affinity and potency at D2 receptors. Such dihydroxyl compounds turned out to be potent inhibitors against aggregation and toxicity of recombinant alpha synuclein protein. The work reported here is in line with our overall goal to develop multifunctional dopamine agonist for symptomatic and disease modifying treatment of Parkinson's disease.
Asunto(s)
Agonistas de Dopamina , Receptores de Dopamina D2 , alfa-Sinucleína , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/química , Piperazinas/farmacología , Receptores de Dopamina D1 , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/agonistasRESUMEN
A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.
Asunto(s)
Discinesias , Levodopa , Animales , Ratas , Ratones , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D1/agonistas , Dopamina , Receptores Acoplados a Proteínas G , LigandosRESUMEN
BACKGROUND: Patients with Parkinson's disease (PD) show impaired performance in taste recognition tests, which suggests a possible dopaminergic influence on gustatory functioning. To experimentally test this hypothesis, we assessed whether pharmacological manipulation of dopaminergic signaling in healthy volunteers can affect performance in a standardized taste recognition test. METHODS: Physically and mentally healthy volunteers (n = 40, age 18-43 years) were randomly allocated to treatment with either pramipexole or placebo using a double-blind, parallel-group design. After 12 to 15 days of treatment (dose titrated up from 0.25 mg/d of pramipexole salt to 1.0 mg/d), taste recognition performance was assessed using a standardized and validated assay (taste strip test). Additionally, visual analogue scale ratings of subjective pleasantness and disgustingness of taste samples were obtained. RESULTS: Compared with the placebo group, participants receiving pramipexole showed significantly higher total recognition accuracy (medianpramipexole = 14.0, medianplacebo = 13.0, U = 264.5, P = .04). This was driven by a higher sensitivity for taste in the pramipexole group. Exploratory analysis of pleasantness and disgustingness ratings of appetitive (sweet) vs aversive (bitter) stimuli suggested that pramipexole treatment was associated with overall blunted hedonic responses, but this effect did not survive the inclusion of nausea (a side effect of treatment) as a covariate in the analysis. CONCLUSIONS: Healthy volunteers who received subacute pramipexole treatment exhibited higher taste recognition performance compared with the placebo group. This finding is consistent with a proposed role of the dopaminergic system in gustatory functioning and could have important theoretical and clinical implications.
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Agonistas de Dopamina , Pramipexol , Receptores de Dopamina D3 , Adolescente , Adulto , Benzotiazoles/efectos adversos , Dopamina , Agonistas de Dopamina/efectos adversos , Método Doble Ciego , Voluntarios Sanos , Humanos , Receptores de Dopamina D3/agonistas , Gusto , Adulto JovenRESUMEN
Pramipexole is a potent agonist of D3 and D2 dopamine receptors, currently approved for clinical use in Parkinson's disease (PD) and restless leg syndrome. Several studies have shown that pramipexole significantly increases the risk of pathological gambling and impulse-control disorders. While these iatrogenic complications can impose a severe social and financial burden, their treatment poses serious clinical challenges. Our group previously reported that the steroidogenic inhibitor finasteride reduced pathological gambling severity in PD patients who developed this complication following pramipexole treatment. To study the mechanisms underlying these effects, here we tested the impact of finasteride in a rat model of pramipexole-induced alterations of probability discounting. We previously showed that, in rats exposed to low doses of the monoamine-depleting agent reserpine (1 mg/kg/day, SC), pramipexole (0.3 mg/kg/day, SC) increased the propensity to engage in disadvantageous choices. This effect was paralleled by a marked D3 receptor upregulation in the nucleus accumbens. First, we tested how finasteride (25-50 mg/kg, IP) intrinsically affects probability discounting. While the highest dose of finasteride produced a marked lack of interest in lever pressing (manifested as a significant increase in omissions), the 25 mg/kg (IP) dose did not intrinsically modify probability discounting. However, this finasteride regimen significantly reduced the adverse effects of reserpine and pramipexole in probability discounting by diminishing rats' propensity to engage in highly disadvantageous probabilistic choices. The same regimen also reversed the upregulation of D3 receptors in the nucleus accumbens induced by reserpine and pramipexole. These findings confirm that finasteride opposes the impulsivity caused by pramipexole and suggest that this effect may be underpinned by a normalizing effect on D3 receptor expression in the nucleus accumbens.
Asunto(s)
Inhibidores de 5-alfa-Reductasa/farmacología , Conducta de Elección/efectos de los fármacos , Agonistas de Dopamina/farmacología , Finasterida/farmacología , Conducta Impulsiva/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Pramipexol/farmacología , Aprendizaje por Probabilidad , Receptores de Dopamina D3/efectos de los fármacos , Receptores de Dopamina D3/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas , Receptores de Dopamina D3/agonistasRESUMEN
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.
Asunto(s)
Antiparkinsonianos/toxicidad , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/toxicidad , Trastornos Parkinsonianos/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Callithrix , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Discinesia Inducida por Medicamentos/prevención & control , Células HEK293 , Humanos , Ligandos , Trastornos Parkinsonianos/prevención & control , Primates , Estructura Secundaria de Proteína , Quinpirol/farmacología , Quinpirol/uso terapéutico , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/químicaRESUMEN
The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Animales , Axones/patología , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/metabolismo , Depresión/etiología , Depresión/prevención & control , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/psicología , Femenino , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Ganglios Linfáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Estrés Oxidativo , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Pramipexol/farmacología , Pramipexol/uso terapéutico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Método Simple Ciego , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains µ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D3R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D3R. Structure-activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.
Asunto(s)
Antagonistas de Dopamina/química , Ligandos , Receptores de Dopamina D3/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/uso terapéutico , Animales , Sitios de Unión , Compuestos de Bifenilo/química , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/uso terapéutico , Modelos Animales de Enfermedad , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/uso terapéutico , Diseño de Fármacos , Transferencia Resonante de Energía de Fluorescencia , Ratones , Simulación del Acoplamiento Molecular , Trastornos Relacionados con Opioides/tratamiento farmacológico , Dolor/tratamiento farmacológico , Manejo del Dolor , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Relación Estructura-ActividadRESUMEN
Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient's key symptoms.