RESUMO
Previously, we have demonstrated that enone prodrugs of dopaminergic catecholamines represent a new type of dopamine (DA) agonist. Trans-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (TL-334), the active form of trans-1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (GMC-6650), in vivo showed an extremely potent dopaminergic activity. Here, we report a novel synthesis and a pharmacological evaluation of TL-334 by means of microdialysis.
Assuntos
Quinolinas/química , Quinolinas/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Animais , Química Encefálica , Linhagem Celular , Diálise , Agonistas de Dopamina/síntese química , Humanos , Microquímica/métodos , Quinolinas/síntese química , TransfecçãoRESUMO
Enone prodrugs of dopaminergic catecholamines represent a new type of prodrug in the research area of dopamine agonists. Here, we demonstrate the first benzo[g]quinoline-derived enone that induces potent dopamine agonist effects similar to aminotetralin-derived enones. Significant effects of (-)-4 were observed in microdialysis studies after administration of 1 nmol kg(-1) sc and 3 nmol kg(-1) po. With a potency comparable to that of the most potent apomorphines, (-)-4 could potentially compete with L-DOPA and apomorphine in the treatment of Parkinson's disease.
Assuntos
2-Naftilamina/análogos & derivados , Agonistas de Dopamina/síntese química , Pró-Fármacos/síntese química , Quinolinas/síntese química , Quinolonas/síntese química , 2-Naftilamina/química , Administração Oral , Animais , Corpo Estriado/metabolismo , Cristalografia por Raios X , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Técnicas In Vitro , Microdiálise , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Pharmacokinetics and dopaminergic effect of dopamine agonist 5-OH-DPAT in vivo were determined following transdermal iontophoresis in rats based on drug concentration in plasma (C(p)) and dopamine levels in striatum (C(DA)). Correlation of the in vitro transport with the pharmacokinetic-pharmacodynamic (PK-PD) profiles was characterized in the transport in dermatomed rat skin (DRS) and rat stratum corneum (RSC). The integrated in vivo PK-PD and in vitro transport models successfully described time course of C(p), C(DA), and in vitro flux in DRS and RSC. Population value of steady-state flux (J(ss)) in vivo (31 nmol/cm(2) . h with 95% confidence interval (CI) = 20-41) is closer to J(ss) in vitro in DRS (61 nmol/cm(2) . h, CI = 54-67) than in vitro J(ss) in RSC (98 nmol/cm(2) . h, CI = 79-117). On the other hand, skin release rate constant (K(R)) in vivo was similar to the K(R) in RSC (4.8/h, CI = 2.4-7.1 vs. 2.6/h, CI = 2.5-2.6). Kinetic lag time (t(L)) in vivo was negligible, which is close to in vitro t(L) in RSC (0.0 h, CI = 0.0-0.1). Based on nonlinear mixed-effect modeling, profiles of C(p) and C(DA) were successfully predicted using in vitro values of J(ss) in DRS with K(R) and t(L) in RSC. A considerable dopaminergic effect was achieved, indicating the feasibility to reach therapeutically effective concentrations of 5-OH-DPAT upon transdermal iontophoresis.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/análogos & derivados , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/farmacocinética , Modelos Biológicos , Pele/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/sangue , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacocinética , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Administração Cutânea , Animais , Dopamina/biossíntese , Agonistas de Dopamina/sangue , Iontoforese , Masculino , Microdiálise , Ratos , Ratos Wistar , Reprodutibilidade dos TestesRESUMO
UNLABELLED: While searching for a PET method to determine the density and occupancy of the dopamine D(3) receptor, we found evidence that suggested that the dopamine D(3) antagonist GR218231 could be a substrate of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions. METHODS: As a potential PET tracer, GR218231 was labeled with (11)C by reaction of the newly synthesized desmethyl precursor with (11)C-methyl triflate. The biodistribution of (11)C-GR218231 was determined in rats. To assess specific binding to the dopamine D(3) receptor, blocking experiments with unlabeled GR218231 (0.2 and 2.5 mg/kg) were performed. To demonstrate the influence of P-glycoprotein on cerebral uptake of (11)C-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of (11)C-GR218231 for P-glycoprotein modulation was assessed in dose-response studies, using escalating cyclosporine A dosages. RESULTS: (11)C-GR218231 was prepared in 53% +/- 8% decay-corrected radiochemical yield and had a specific activity of 15 +/- 10 GBq/micromol (mean +/- SD). Biodistribution studies in rats revealed a low and homogeneous uptake in the brain. Pretreatment of the animals with unlabeled GR218231 did not demonstrate any specific binding. Modulation of P-glycoprotein with cyclosporine A caused a 12-fold higher (11)C-GR218231 uptake in the brain, indicating that the low cerebral tracer uptake was caused by the P-glycoprotein efflux pump in the blood-brain barrier. Cyclosporine A dose-escalation studies showed a dose-dependent sigmoidal increase in (11)C-GR218231 uptake in brain and spleen (median effective dose [ED(50)], 23.3 +/- 0.6 and 38.4 +/- 2.4 mg/kg, respectively), whereas a dose-dependent decrease was observed in the pancreas (ED(50), 36.0 +/- 4.4 mg/kg). CONCLUSION: Although (11)C-GR218231 is unsuited for dopamine D(3) receptor imaging with PET, it appears to be an attractive PET tracer for visualization and quantification of P-glycoprotein activity in the blood-brain barrier.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Antagonistas dos Receptores de Dopamina D2 , Receptores de Dopamina D2/metabolismo , Sulfonas/farmacocinética , Tetra-Hidronaftalenos/farmacocinética , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Marcação por Isótopo/métodos , Masculino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Receptores de Dopamina D3 , Sulfonas/química , Tetra-Hidronaftalenos/química , Distribuição TecidualRESUMO
The feasibility of transdermal iontophoretic delivery of a potent dopamine agonist 5-OH-DPAT was studied in vitro in side by side diffusion cells across human stratum corneum (HSC) and dermatomed human skin (DHS) according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis and 5 h of passive diffusion. The influences of the following parameters on the flux were studied: donor solution pH, NaCl concentration, drug donor concentration, current density and skin type. A current density of 0.5 mA cm(-2) was used, except for one series of experiments to study the current density effect. Probably due to the influence of the skin perm-selectivity and the competition with H(+), increase in pH from 3 to 5 resulted in a significant increase in flux. Further increase in pH to 6 did not further increase the flux. The iontophoretic transport was found to increase linearly with concentration and current density, providing a convenient way to manage dose titration for Parkinson's disease therapy. Increase in concentration of NaCl dramatically reduced the flux of 5-OH-DPAT as a result of ion competition to the transport. When DHS was used, the iontophoretic transport was less. Also, with DHS the response in flux profile, by switching the current on and off, was shallower than that with HSC. With the optimum condition, a delivery of 104 microg of 5-OH-DPAT per cm(2) patch per hour is feasible, indicating that the therapeutic level could be achieved with a smaller patch size than required in case of rotigotine. Thus, based on this in vitro study, transdermal iontophoretic delivery of 5-OH-DPAT is very promising.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/análogos & derivados , Agonistas de Dopamina/farmacocinética , Iontoforese , Pele/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacocinética , Agonistas de Dopamina/administração & dosagem , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Absorção Cutânea/efeitos dos fármacosRESUMO
In in vivo positron emission tomography (PET) studies, dopamine that is released secondary to amphetamine administration appears unable to achieve a receptor occupancy that is significantly higher than 50% ("ceiling effect"). Also with exogenous agonists no studies have reported a higher than 50% occupancy. To investigate the feasibility of exceeding 50% occupancy in vivo with a dopamine receptor agonist we administered D2/D3 agonist (+)-PD 128907 over an extensive dose range. Two anesthetised Macaca mulatta males were used in a bolus-infusion protocol for [(11)C]raclopride. (+)-PD 128907 was administered as an intravenous challenge during separate PET scans in a dose range of 10 to 10000 nmol/kg. Occupancy by (+)-PD 128907 was estimated by comparing the binding before and after challenge. In a striatal region of interest, receptor occupancy by (+)-PD 128907 increased in an orderly dose-dependent manner to a maximum of at least 85%. This is the first indication that virtually all dopamine D2/D3 receptors in the striatum are in principle accessible to agonist binding. In the case of dopamine a number of protective mechanisms may be responsible for the ceiling effect.
Assuntos
Benzopiranos/metabolismo , Agonistas de Dopamina/metabolismo , Antagonistas de Dopamina/metabolismo , Oxazinas/metabolismo , Racloprida/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Relação Dose-Resposta a Droga , Macaca mulatta , Masculino , Tomografia Computadorizada de EmissãoRESUMO
The present study describes the synthesis and in vitro pharmacology of a novel series of dopaminergic agents in which the classical phenylethylamine pharmacophore is replaced by a thienylethylamine moiety. In general, the novel compounds showed a moderate affinity for the dopamine (DA) D(2) and D(3) receptors. When the thienylethylamine moiety is fixed in a rigid system, the affinity for the DA receptor is significantly increased. However, in the tricyclic hexahydrothianaphthoxazine structure, the affinity for the DA receptors is diminished.
Assuntos
Agonistas de Dopamina/síntese química , Receptores de Dopamina D2/metabolismo , Tiofenos/síntese química , Animais , Ligação Competitiva , Disponibilidade Biológica , Células CHO , Cricetinae , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Microdiálise , Ensaio Radioligante , Ratos , Receptores de Dopamina D3 , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
A series of racemic and enantiomerically pure oxime derivatives of the potential anti-Parkinson prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (1) were synthesized and pharmacologically evaluated. The oximes induced rotational behavior in the Ungerstedt rat rotation model for Parkinson's disease after oral administration. Especially the unsubstituted oxime ((-)-3) and the acetyl-oxime ((-)-10) induced a pronounced and long lasting effect. In this model, large individual differences were observed in responsiveness to treatment between rats. Though less potent than the parent prodrug, the oxime derivatives of (+/-)-1 and (-)-1 can be orally active, acting as cascade prodrugs.
Assuntos
Dopaminérgicos/síntese química , Dopaminérgicos/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Oximas/síntese química , Oximas/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Administração Oral , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Células CHO , Linhagem Celular , Cricetinae , Modelos Animais de Doenças , Dopaminérgicos/química , Feixe Prosencefálico Mediano/lesões , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Naftalenos/química , Neurônios/citologia , Oxidopamina/toxicidade , Oximas/química , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Pró-Fármacos/química , Ratos , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estereoisomerismo , TransfecçãoRESUMO
A series of analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (6), an enone prodrug of the mixed DA D(1)/D(2) agonist 5,6-diOH-DPAT (2), was synthesized. The pharmacological profiles of these new enones and their in vivo pharmacological activities were investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg(-1) po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronounced and long lasting pharmacological effects. The pharmacological profile of enone 12 was found to be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01). Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence of hydroxylated metabolites of the parent enones. It is speculated that such metabolites are alpha'-hydroxylated enones that may constitute the first step in the formation of the corresponding catechols.
Assuntos
2-Naftilamina/síntese química , Antiparkinsonianos/síntese química , Agonistas de Dopamina/síntese química , Naftalenos/síntese química , Pró-Fármacos/síntese química , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , 2-Naftilamina/farmacologia , Administração Oral , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Encéfalo/metabolismo , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Ligantes , Masculino , Atividade Motora/efeitos dos fármacos , Naftalenos/química , Naftalenos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Ratos Wistar , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade , Tomografia Computadorizada de EmissãoRESUMO
After decades of research around dopamine agonists, we have found a promising compound in S-PD148903 that represents a new type of prodrug, which in the rat is bioactivated to the catecholamine S-5,6-diOH-DPAT, known to display mixed dopamine D(1)/D(2) receptor agonist properties just like apomorphine. This prodrug has an enone structure which by an oxidative bioactivation mechanism is converted to the corresponding catechol and is delivered enantioselectively into the CNS. This novel concept has the potential to revolutionize the treatment of Parkinson's disease by competing with L-DOPA, the current treatment of choice.
Assuntos
2-Naftilamina/síntese química , Antiparkinsonianos/síntese química , Catecolaminas/síntese química , Doença de Parkinson/tratamento farmacológico , Pró-Fármacos/síntese química , Tetra-Hidronaftalenos/metabolismo , 2-Naftilamina/análogos & derivados , 2-Naftilamina/metabolismo , 2-Naftilamina/farmacologia , Administração Oral , Animais , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacologia , Catecolaminas/metabolismo , Catecolaminas/farmacologia , Cristalografia por Raios X , Masculino , Microdiálise , Conformação Molecular , Doença de Parkinson/fisiopatologia , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/administração & dosagemRESUMO
The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the active (S)-enantiomer of the potent dopamine (DA) agonist 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT) were investigated in a novel anesthetized animal model. First, the relationship between current density, in vivo transport, and plasma profile was characterized. Second, the effect of the anesthetic mixture, transdermal iontophoresis, and blood sampling on the striatal DA release (PD end point) was investigated. Third, the PK-PD relationship following transdermal iontophoresis was investigated during a controlled reversible pharmacological response. Given that striatal DA levels are unaltered during experimental procedures, this rat model can be used to investigate the PK-PD relationship. The in vivo flux was linearly correlated with the current density, indicating that drug delivery can be titrated by the current density. Following transdermal iontophoresis and intravenous infusion, a strong reversible effect was observed. Compartmental modeling showed that the relationship between plasma concentration and biomarker response is best characterized by an effect compartment, rather than an indirect response model. In addition, covariate analysis suggested that the delivery rate can affect the PD efficiency. Finally, PK-PD analysis revealed that steady delivery rates are translated into continuous dopaminergic stimulation. This can be of benefit for reducing side effects in the symptomatic treatment of Parkinson's disease with 5-OH-DPAT.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/análogos & derivados , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Gânglios da Base/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacocinética , Iontoforese , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/sangue , 8-Hidroxi-2-(di-n-propilamino)tetralina/química , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacocinética , Administração Cutânea , Anestésicos Inalatórios/farmacologia , Animais , Antiparkinsonianos/sangue , Antiparkinsonianos/química , Gânglios da Base/metabolismo , Preparações de Ação Retardada , Difusão , Dopamina/metabolismo , Agonistas de Dopamina/sangue , Agonistas de Dopamina/química , Infusões Intravenosas , Isoflurano/farmacologia , Masculino , Microdiálise , Modelos Biológicos , Dinâmica não Linear , Ratos , Ratos WistarRESUMO
OBJECTIVES: The transdermal iontophoretic delivery of a novel series of 2- aminotetralins and chromanamine-based dopamine agonists was investigated in vitro. METHODS: Systematic structural modifications allowed us to investigate their effect on solubility in the donor phase and iontophoretic delivery across human skin. Transport profiles were analysed with nonlinear mixed effect modelling, utilizing an extension to an existing compartmental model. Furthermore, relationships between physicochemical properties and transport parameters were addressed. KEY FINDINGS: A solubility increase was observed: 5,6-di-OH-DPAT < 5-OH-MPAT < 5-OH-EPAT < 8-OH-DPAC. The structure significantly affected the iontophoretic delivery across human stratum corneum and dermatomed human skin with the highest flux for 5-OH-EPAT and 5-OH-MPAT. The extended model with two skin release constants (K(R1), K(R2)) described more adequately iontophoretic transport profiles than the existing model with one release constant. The extended model suggested two parallel transport pathways during current application. Across human stratum corneum, the electrophoretic mobility, measured with capillary electrophoresis, showed a linear relationship with the electromigrative flux and the zero-order iontophoretic mass input into the skin (I(0)). CONCLUSIONS: Combining transport parameters (I(0), K(R1) and K(R2)), predicted from physicochemical properties, with compartmental modelling provided a powerful tool to simulate iontophoretic transport profiles for screening potential candidates and designing experiments.
Assuntos
Cromanos/farmacocinética , Agonistas de Dopamina/farmacocinética , Absorção Cutânea , Tetra-Hidronaftalenos/farmacocinética , Transporte Biológico , Cromanos/administração & dosagem , Cromanos/química , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/química , Desenho de Fármacos , Eletroforese Capilar , Humanos , Iontoforese , Modelos Biológicos , Dinâmica não Linear , Solubilidade , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/químicaRESUMO
A characterization and optimization of the in vitro transdermal iontophoretic transport of 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT) is presented. The utility of acetaminophen as a marker of electroosmotic flow was studied as well. The following parameters of iontophoretic transport of 5-OH-DPAT were examined: drug donor concentration, electroosmotic contribution, influence of co-ions, current density, and composition of the acceptor phase. The steady-state flux (Flux(ss)) of acetaminophen was linearly correlated with the donor concentration and co-iontophoresis of acetaminophen did not influence the iontophoretic flux of 5-OH-DPAT, indicating that acetaminophen is an excellent marker of electroosmotic flow. Lowering the Na(+) concentration from 78 to 10 mM in the donor phase, resulted in a 2.5-fold enhancement of the Flux(ss). The Flux(ss) showed a nonlinear relation with the drug donor concentration and an excellent linear correlation with the current density. Reducing the pH of the acceptor phase from 7.4 to 6.2 resulted in a dramatic decrease of the Flux(ss) of 5-OH-DPAT, explained by a reduced electroosmotic flow and an increased counter-ion flow. Optimization of the conditions resulted in a maximum Flux(ss) of 5-OH-DPAT of 1.0 micromol x cm(-2) h(-1) demonstrating the potential of the iontophoretic delivery of this dopamine agonist for the symptomatic treatment of Parkinson's disease.