RESUMO
The Fawn-hooded rat has long been used as a model for various peripheral and central disorders and the data available indicate that the social behavior of this strain may be compromised. However, a thorough description of the Fawn-hooded rat is unavailable in this regard. The objective of the present study was to investigate various aspects of the Fawn-hooded rat's social behavior in depth. Our results show that several facets of socio-communicational behavior are impaired in the RjIbm(m):FH strain, including defective ultrasonic vocalizations in pups upon maternal deprivation, reduced social play in adolescence and impaired social novelty discrimination in adulthood. In addition, Fawn-hooded rats exhibited heightened tactile sensitivity and hyperactivity. The defects observed were comparable to those induced by prenatal valproate exposure, a widely utilized model of autism spectrum disorder. Further on, the pro-social drug R-baclofen (0.25-1 mg/kg) reversed the autistic-like defects observed in Fawn-hooded rats, specifically the deficiency in ultrasonic vocalization, tactile sensitivity and social novelty discrimination endpoints. In conclusion, the asocial, hypersensitive and hyperactive phenotype as well as the responsivity to R-baclofen indicate this variant of the Fawn-hooded rat strain may serve as a model of autism spectrum disorder and could be useful in the identification of novel drug candidates.
RESUMO
The systemic use of GABAB orthosteric agonist baclofen might be limited due to its detrimental properties: sedation and motor impairment. In contrast, GABAB positive allosteric modulators produce less adverse effects. Using BHF-177 as a starting point, we found a new active scaffold: the 6-aryl-quinazoline scaffold. Further elaborating the scaffold, we identified several in vitro and in vivo active compounds.
Assuntos
Agonistas dos Receptores de GABA-B , Receptores de GABA-B , Regulação Alostérica , Baclofeno , Agonistas dos Receptores de GABA-B/farmacologia , Quinazolinas/farmacologiaRESUMO
A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure-activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies.
Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas , Pirazinas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Benzimidazóis/química , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirazinas/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy. METHODS: In vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. RESULTS: Similar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine. CONCLUSION: Overall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.
Assuntos
Piperazinas/farmacologia , Animais , Antipsicóticos/farmacologia , Encéfalo/metabolismo , Células CHO , Cricetulus , AMP Cíclico/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Piperazinas/metabolismo , Piperazinas/farmacocinética , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina , Receptor 5-HT2B de Serotonina , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de SinaisRESUMO
While cerebellar alterations may play a crucial role in the development of core autism spectrum disorder (ASD) symptoms, their pathophysiology on the function of cerebrocerebellar circuit loops is largely unknown. We combined multimodal MRI (9.4 T) brain assessment of the prenatal rat valproate (VPA) model and correlated immunohistological analysis of the cerebellar Purkinje cell number to address this question. We hypothesized that a suitable functional MRI (fMRI) paradigm might show some altered activity related to disrupted cerebrocerebellar information processing. Two doses of maternal VPA (400 and 600 mg/kg, s.c.) were used. The higher VPA dose induced 3% smaller whole brain volume, the lower dose induced 2% smaller whole brain volume and additionally a focal gray matter density decrease in the cerebellum and brainstem. Increased cortical BOLD responses to whisker stimulation were detected in both VPA groups, but it was more pronounced and extended to cerebellar regions in the 400 mg/kg VPA group. Immunohistological analysis revealed a decreased number of Purkinje cells in both VPA groups. In a detailed analysis, we revealed that the Purkinje cell number interacts with the cerebral BOLD response distinctively in the two VPA groups that highlights atypical function of the cerebrocerebellar circuit loops with potential translational value as an ASD biomarker.
Assuntos
Transtorno Autístico/patologia , Células de Purkinje/patologia , Ácido Valproico/efeitos adversos , Animais , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/fisiopatologia , Calbindinas/metabolismo , Contagem de Células , Modelos Animais de Doenças , Feminino , Imageamento por Ressonância Magnética , Células de Purkinje/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.
Assuntos
Quinolinas/química , Quinolinas/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Aminação , Animais , Humanos , Piperazinas/química , Piperazinas/farmacologia , Ratos WistarRESUMO
Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.
Assuntos
Ansiolíticos/química , Ansiolíticos/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Ansiolíticos/uso terapêutico , Cães , Feminino , Halogenação , Humanos , Macaca fascicularis , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Simulação de Acoplamento Molecular , Nitrilas/uso terapêutico , Quinolinas/uso terapêutico , RatosRESUMO
High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability. One of the most promising compounds (3), showing excellent in vivo efficacy, was selected for preclinical development and subsequent phase I clinical studies.
Assuntos
Quinolinas/química , Receptor de Glutamato Metabotrópico 5/química , Regulação Alostérica , Animais , Doenças do Sistema Nervoso Central/etiologia , Ensaios de Triagem em Larga Escala , Humanos , Ligação Proteica , Quinolinas/síntese química , Quinolinas/metabolismo , Quinolinas/toxicidade , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.
Assuntos
Ligantes , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2C de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Animais , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Permeabilidade/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
An HTS campaign of our corporate compound library, and hit-to lead development resulted in thieno[2,3-b]pyridine derivative leads with mGluR5 negative allosteric modulator effects. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modification of the first two targeted regions resulted in compounds with nanomolar affinity, then optimal substitution of the third region improved metabolic stability. One of the most promising compounds showed excellent in vivo efficacy and is a potential development candidate.
Assuntos
Pirimidinas/química , Receptor de Glutamato Metabotrópico 5/química , Regulação Alostérica , Animais , Ensaios de Triagem em Larga Escala , Humanos , Ligação Proteica , Pirimidinas/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
The aim of the present paper was to study the effects of GABAA receptor-positive modulators (L-838417 and NS11394) showing a preference for α2/3 subunits of the GABAA receptor, in models of pain, anxiety, learning, memory and motor function. These compounds have been suggested to have a favourable therapeutic profile over nonselective compounds such as diazepam. In this study, we tested both compounds for their effects in rat models of formalin-induced pain, spinal nerve-ligation-induced mechanical allodynia, plus maze, open field, rotarod, balance beam walking, contextual fear conditioning and Morris water maze. Both compounds exerted analgesic, but no anxiolytic effects. However, they induced motor side-effects, and learning and memory impairment at similar doses. Therefore, the anxiolytic effect and the lack of side-effects of these compounds, as described in the literature, could not be confirmed in the present study.
Assuntos
Benzimidazóis/farmacologia , Fluorbenzenos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Triazóis/farmacologia , Regulação Alostérica , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Analgésicos/toxicidade , Animais , Ansiedade/tratamento farmacológico , Benzimidazóis/administração & dosagem , Benzimidazóis/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medo , Fluorbenzenos/administração & dosagem , Fluorbenzenos/toxicidade , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Atividade Motora , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Triazóis/administração & dosagem , Triazóis/toxicidadeRESUMO
Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012.
Assuntos
Antipsicóticos/farmacologia , Piperazinas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D4/efeitos dos fármacos , Animais , Antipsicóticos/farmacocinética , Área Sob a Curva , Humanos , Piperazinas/farmacocinética , RatosRESUMO
We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N',N'-dimethyl-urea), a D(3)/D(2) dopamine receptor partial agonist with â¼10-fold preference for the D(3) receptor. Oral bioavailability of cariprazine at a dose of 1mg/kg in rats was 52% with peak plasma concentrations of 91ng/mL. Cariprazine 10mg/kg had good blood-brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [(3)H](+)-PHNO, a dopamine D(3) receptor-preferring radiotracer, in the D(3) receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED(50)=0.27mg/kg) was sustained for 8h. Cariprazine blocked amphetamine-induced hyperactivity (ED(50)=0.12mg/kg) and conditioned avoidance response (CAR) (ED(50)=0.84mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED(50)=0.049mg/kg) and phencyclidine (ED(50)=0.09mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED(50)=0.11mg/kg) and rats (ED(50)=0.18mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED(50) value. Cariprazine 0.02-0.08mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D(3) receptors versus currently marketed typical and atypical antipsychotics.
Assuntos
Antipsicóticos/farmacologia , Nootrópicos/farmacologia , Piperazinas/metabolismo , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/metabolismo , Animais , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Ligação Proteica/fisiologia , Ratos , Ratos Wistar , Receptores de Dopamina D3/fisiologiaRESUMO
5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis. The aim of this study was to investigate the efficacy of the selective 5-HT6 antagonists, Ro-4368554 (1-10 mg/kg, intraperitoneally) and SB-258585 (3-30 mg/kg, intraperitoneally), in animal models for schizophrenia and AD. Both compounds showed cognition-enhancing effects in object recognition, whereas only SB-258585 was able to prevent the scopolamine-induced deficit in the Morris water-maze test. Neither Ro-4368554 nor SB-258585 prevented scopolamine-induced impairment in contextual fear conditioning. Similarly, both compounds were ineffective on MK-801-induced deficits in contextual fear conditioning and spatial working memory. Ro-4368554, but not SB-258585 reversed the apomorphine-induced deficit in prepulse inhibition. Amphetamine-induced hyperlocomotion was not affected by either compound. Taken together, the overall efficacy of Ro-4368554 and SB-258585 in animal models for AD and schizophrenia is rather limited. These data show moderate efficacy in some models for AD but do not support the therapeutic potential of 5-HT6 antagonists for schizophrenia.
Assuntos
Indóis/farmacologia , Piperazinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Anfetamina/toxicidade , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medo/efeitos dos fármacos , Hipercinese/induzido quimicamente , Indóis/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Piperazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Antagonistas da Serotonina/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
Hit-to-lead optimization of a HTS hit led to new carbamoyloxime derivatives. After identification of an advanced hit (8d) the CYP enzyme inhibitory activity of this class of compounds was successfully eliminated. Systematic exploration of different parts of the advanced hit led us to some promising lead compounds with mGluR5 affinities comparable to that of MPEP.
Assuntos
Carbamatos/química , Oximas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Carbamatos/síntese química , Carbamatos/farmacologia , Ensaios de Triagem em Larga Escala , Oximas/síntese química , Oximas/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Especificidade por SubstratoRESUMO
RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) -piperazine -1 -yl] -ethyl] -cyclohexyl] -3 -pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D3/D2 receptor antagonist with subnanomolar affinity for the D3 receptor and nanomolar affinity for the D2 receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED50 (median effective dose) values of 8.6 and 12 mg/kg orally, respectively. At six- to eightfold higher doses, RG-15 blocked spontaneous motor activity, while a 30 mg/kg dose of the compound caused an increase in the home-cage motility of rats. The drug did not produce catalepsy up to 160 mg/kg oral dose; moreover, it inhibited haloperidol-induced catalepsy in the range 15-60 mg/kg. RG-15 (10 mg/kg orally) restored the impaired learning performance of scopolamine- or diazepam-treated rats in a water-labyrinth paradigm. It is assumed that the motor activating, anticataleptic and cognitive-enhancing properties of RG-15 result from its potent D3 antagonism. In this regard, RG 15 clearly differs from other antipsychotics. Olanzapine, clozapine and amisulpride all showed efficacy against amphetamine-induced hyperactivity and on conditioned avoidance, but compared to RG-15, they proved to be more cataleptogenic and depressed or did not change the home-cage activity of animals. Olanzapine was also inactive in the learning paradigm. Our results suggest that subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity may result in an antipsychotic profile characterised by a lack of extrapyramidal side effects and secondary negative symptoms with simultaneous efficacy on positive and cognitive symptoms of schizophrenia.
Assuntos
Antipsicóticos/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Antagonistas dos Receptores de Dopamina D2 , Receptores de Dopamina D3/antagonistas & inibidores , Amissulprida , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/toxicidade , Aprendizagem da Esquiva/efeitos dos fármacos , Benzodiazepinas/farmacologia , Disponibilidade Biológica , Catalepsia/induzido quimicamente , Clozapina/farmacologia , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/toxicidade , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Olanzapina , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridinas/toxicidade , Ratos , Ratos Wistar , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade , Sulpirida/análogos & derivados , Sulpirida/farmacologia , Distribuição TecidualRESUMO
A novel series of arylsulfonamides was prepared either by automated parallel or by traditional solution-phase synthesis. Several members of this compound library were identified as high-affinity dopamine D3 and D2 receptor ligands. The most interesting representative, compound 2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile.
Assuntos
Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Antipsicóticos/metabolismo , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Disponibilidade Biológica , Encéfalo/metabolismo , Catalepsia/induzido quimicamente , Humanos , Indicadores e Reagentes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacos , Sulfonamidas/metabolismoRESUMO
SB 277011-A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide) and S 33084 [(3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl](4-phenyl)benzamide] were already shown to lack cataleptogenic actions. Further to that, we report that SB 277011 exerted a dose-dependent dampening on the development of haloperidol-induced catalepsy in the dose-range of 13.5-30 mg/kg p.o. while S 33084, at the dose of 0.625 mg/kg sc. significantly inhibited catalepsy induced by haloperidol; had no effect at 1.25 mg/kg, and further augmented the effect of haloperidol after 2.5 mg/kg. The compounds also produced effective inhibition when administered 2 hours after haloperidol. The results underline that dopamine D3 receptor antagonist action may have therapeutic value in the treatment of schizophrenia.
Assuntos
Benzopiranos/farmacologia , Catalepsia/tratamento farmacológico , Nitrilas/farmacologia , Pirróis/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologia , Animais , Catalepsia/induzido quimicamente , Haloperidol , Masculino , Ratos , Ratos WistarRESUMO
Dopamine D(3) receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D(3) receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K(i) = 6.7 nM) and rat (K(i) = 1.6 nM) D(3) receptors with an intrinsic activity of approximately 50%. It possessed several hundredfold selectivity over the D(2) receptor. The molecule bound with moderate (100-250 nM) affinity to 5-hydroxytryptamine 1A (5-HT(1A)) and nonselectively labeled opiate receptors. RGH-237 proved to be practically inactive on more than 40 other targets, including monoaminergic, cholinergic, GABAergic, and glutamatergic receptors. In rats orally administered RGH-237 was well and rapidly absorbed yielding 41% oral bioavailability. At its pharmacologically active dose (10 mg/kg p.o.), the brain concentration of RGH-237 reached 110 ng/g. Its blood and brain levels were sustained for 3 h. RGH-237 at the oral dose of 10 mg/kg moderately but significantly inhibited the acquisition of cocaine-induced place preference, although by itself, it had no place-conditioning effect. The compound did not affect fixed ratio 1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration, the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behavior of rats at 10 and 30 mg/kg oral doses. RGH-237 did not affect seeking activity for natural rewards, such as sucrose and water. It did not exert notable effect on spontaneous motor activity of rats. Our results demonstrate that selective D(3) partial agonists may be an effective therapeutic means in the treatment of cocaine abuse.