Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

The role of dopamine D3 receptor in perimenopausal depression / 西安交通大学学报(医学版)

【Objective】 To investigate the role of dopamine D3 receptor deficiency in depression-like behavior in perimenopausal depression and to explore the role of dopamine D3 receptor in the pathogenesis of perimenopausal depression. 【Methods】 Based on the perimenopausal depression animal model， RT-PCR was used to study the changes of D3 receptor mRNA in the nucleus accumbens （NAc） in mice. Furthermore， dopamine D3 receptor knockout （D3RKO） mice and wild type （WT） mice of the same genetic background were used， respectively. Forced swim test （FST） and tail suspension test （TST） were used to assess depressive-like behavior in mice. 【Results】 D3 receptor mRNA in the NAc decreased significantly in perimenopause （P0.05）. 【Conclusion】 Dopamine D3 receptor in the NAc is significantly decreased during perimenopause. Obvious decrease or deficiency of dopamine D3 receptors may be involved in the regulation of perimenopausal depression.

Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors

Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the β-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced β-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, β-arrestin2, and Gβγ. Gβγ displayed a stable interaction with receptors and β-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between Gβγ and β-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and Gβγ complex is required for the formation of a complex with β-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, β-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and Gβγ.

Functional Regulation of Dopamine D₃ Receptor through Interaction with PICK1

PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine D₃ receptors (D₃R), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine D₂ receptor (D₂R) and D₃R in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of D₂R were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of D₃R were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on D₃R functions.

Roles of Dopamine D₂ Receptor Subregions in Interactions with β-Arrestin2

β-Arrestins are one of the protein families that interact with G protein-coupled receptors (GPCRs). The roles of β-arrestins are multifaceted, as they mediate different processes including receptor desensitization, endocytosis, and G protein-independent signaling. Thus, determining the GPCR regions involved in the interactions with β-arrestins would be a preliminary step in understanding the molecular mechanisms involved in the selective direction of each function. In the current study, we determined the roles of the N-terminus, intracellular loops, and C-terminal tail of a representative GPCR in the interaction with β-arrestin2. For this, we employed dopamine D₂ and D₃ receptors (D₂R and D₃R, respectively), since they display distinct agonist-induced interactions with β-arrestins. Our results showed that the second and third intracellular loops of D₂R are involved in the agonist-induced translocation of β-arrestins toward plasma membranes. In contrast, the N- and C-termini of D₂R exerted negative effects on the basal interaction with β-arrestins.

Association of polymorphisms in dopamine D3 receptor gene with Childhood tourette syndrome and efficacy of aripiprazole / 中华行为医学与脑科学杂志

Objective To investigate the association of polymorphisms in dopamine D3 receptor (DRD3) gene exon 1 Ser9Gly with childhood tourette syndrome and efficacy of aripiprazole in Chinese Han population.Methods Polymorphisms of Ser9Gly in DRD3 gene was genotyped by using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) in 158 tourette syndrome patients (study group) and 187 healthy controls (control group).Patients in study group were assessed with Yale global tic severity scale(YGTSS) at baseline and at the end of the 8th week of treatment to evaluate the efficacy of aripiprazole.Results (1) There were no significant differences in genotypic frequency and allelic frequency of Ser9Gly in DRD3 gene between study group and control group (P＞0.05).(2) Significant difference was found in frequency of Ser9Gly in DRD3 gene between effective and ineffective groups (genotype:Ser/Ser 40 vs 17;Ser/Gly 52 vs 28;Gly/Gly 7 vs 14;alle:Ser 132 vs 62;Gly 66 vs 56)(P＜0.05).(3) There were no significant differences in distribution of genotypes and alleles of Ser9Gly among three-type of tourette syndrome (P＞0.05).Conclusion The polymorphisms of Ser9Gly in DRD3 gene are associated with the efficacy of aripiprazole.

Correlation study on susceptible genes of obsessive compulsive disorder of Han population in northeast China / 中华行为医学与脑科学杂志

Objective To explore the relationship between Monoamine oxidase A (MAOA) receptor gene,catechol-O-methyltransferase (COMT) receptor gene,dopamine D3 receptor(DRD3) gene and 5-HT2C receptor gene(5-HT2c) of Han population in northern China and obsessive compulsive disorder.Methods Polymerase chain reaction amplification determination of MAOA-T1460C,COMT-Val158Met,DRD3-Ser9Gly,5-HT2c-C ys23Ser four loci receptor gene polymorphism in 164 patients with OCD patients including 103 core pedigrees of fragment length polymorphism,and association and linkage disequilibrium (TDT)analysis.Results There was no significant difference of MAOA-T1460C,COMT-Val158Met,DRD3-Ser9Gly,5-HT2c-Cys23Ser four receptor gene in the patient group and the control group of genotype and allele distribution difference(P＞0.05),four receptor gene loci were in accordance with the balance of the H-W,the MAOA-T1460C receptor gene in female patients group and control group,the early group and control group,which has forced thinking and difference of compulsive behavior group and the control group,only the obsessional group and the control group of genotype and allele distribution was statistically significant(P＜0.05),and the family group between chain(P=0.0001) ;5-HT2c-Cys23Ser receptor gene in the case group and the control group,male both forced thinking and compulsive behavior group and control group differences in genotype and allele distribution was statistically significant (P＜ 0.05),and between family groups exist chain (P=0.0389) ; COMT-Val158Met receptor gene in the control experiments were no significant difference(P＞0.05),and with the house group does not exist between the chain (P=0.0622) ;DRD3-Ser9Gly receptor gene in the control experiments were no significant difference(P＞0.05),and with the family groups there is no chain(P=0.1101).Conclusion MAOA-T1460C receptor gene polymorphism and 5-HT2c-Cys23Ser receptor gene polymorphisms may be the susceptible gene of obsessive compulsive disorder.

Progress of dopamine D3 receptors / 国际儿科学杂志

The role of dopamine D3 receptors playing in drug dependence has attracted a lot of attention.Pharmacological experiments suggest that dopamine D3 receptors be involved in mechanism of drug addiction and affect the movement and behavior of rodents. Dopamine D3 receptor gene is considered as a candidate gene related to dopaminergic system dysfunction including schizophrenic disorders and essential tremor.

Association Study between 5-HT2A Receptor and DRD3 Receptor Gene Polymorphism and Clinical Response to Atypical Antipsychotics in Patients with Schizophrenia / 신경정신의학

OBJECTIVES: This study was performed based on the hypothesis that the interindividual differences in clinical response to atypical antipsychotics might be associated with serotonin 2A receptor(5-HT2A) gene and(or) dopamine D3 receptor(DRD3) gene polymorphisms. METHODS: Seventy-five patients(39 men, 36 women) who met DSM-IV criteria for Schizophrenia at the Asan Medical Center were selected for the analysis of the medical records and subsequent interview. A written informed consent was obtained prior to the study and the privacy protection was kept throughout the course. Clinical Global Impression(CGI) Scale was applied after 4 weeks of treatment to assess the response to atypical antipsychotics. All patients in this study were administered olanzapine(n=39), risperidone(n=52) or clozapine(n=4). According to CGI scale, the patients were classified in 7 groups ; very much improvement ; much improvement ; minimal improvement ; no change ; minimal worsening ; much worsening ; very much worsening. The first and second groups were regarded as responders while the other groups were non-responders. Patients were genotyped for 5-HT2A by PCR(Msp I) for detection of T102 and C102 alleles. And they were also genotyped for DRD3 Ser9Gly polymorphism by PCR(Bal I). We conducted the statistical analyses to detect association between responders and non responders with chi-square tests. RESULTS: The patients who were shown no or minimally improved patients were sorted to non-responders(n=42, men 24, women 18) and the other patients shown much or very much improved were grouped as responders(n=33, men 15, women 18). The differences in demographic variables(age, sex), age of onset, and duration of illness were not statistically significant between the two groups. T102 allele is more frequent in non-responders(56.0%) than responders(45.5%), however, this difference is not statistically significant(p=0.20). Gly9 allele is near equal between non-responders and responders (65.5%, 65.2%). Genotype frequencies of the two groups also is not a statistically significant for 5-HT2A T102C(p=0.28) and DRD3 Ser9Gly(p=0.90). CONCLUSION:These results do not show significant associations among 5-HT2A gene, DRD3 gene and clinical response to atypical antipsychotics. On the assumption that responses to atypical antipsychotics are mediated by these two receptors, we can draw two possibilities. First, 5-HT2A and DRD3 genes may not be the functional variants related with responses to atypical antipsychotics. Second possibility is that the unknown variations which might be in linkage disequilibrium with the 5-HT2A T102C polymorphism and DRD3 Ser9Gly polymorphism may be associated with the response to atypical antipsychotics in schizophrenia. However, it is possible that the small number of subjects and ethnic difference of allele frequency of marker polymorphism could induce false negative results.

The Association between Polymorphism of the Dopamine D3 Receptors and Concentrations of Plasma Homovanillic and 5-hydroxyindoleacetic Acid, and Therapeutic Response of chronic Schizophrenic Patients

OBJECTIVES: Schizophrenia manifests a variety of interindividual differences in therapeutic response to antipsychotics. This might be attributable to dopamine and serotonin receptors that a important target for various antipsychotics, and the D3 receptor(DRD3) alleles they carry. The purpose of our study was to investigate whether the plasma levels of homovanillic acid(HVA) and 5-hydroxyindoleacetic acid(HIAA), and the polymorphism of DRD3 can be held as a predictor of treatment response ni chronic schizophrenic patients. METHODS: Therapeutic response for 16 korean schizophrenia patient treated during 48 weeks were assessed by PANSS used as the clinical symptom rating scales. The levels of concentration of HVA and 5-HIAA were examined by HPLC at baseline and at 48 weeks. We classified the polymorphism of DRD3 receptor using amplifying by polymerase chain reaction(PCR). RESULTS: Neither concentrations of HVA and 5-HIAA nor genotype of dopamine 3 receptor were not significantly associated with the therapeutic response. But, the patients who has A1 alleles of DRD3 gene showed poor therapeutic responses. CONCLUSION: A1 allele of DRD3 gene is associated with poor prognosis of chronic schizophrenia.