RESUMEN
Metal-organic frameworks (MOFs) give the opportunity of confining guest molecules into their pores even by a post-synthetic protocol. PUM168 is a Zn-based MOF characterized by microporous cavities that allows the encapsulation of a significant number of guest molecules. The pores engineered with different binding sites show a remarkable guest affinity towards a series of natural essential oils components, such as eugenol, thymol and carvacrol, relevant for environmental applications. Exploiting single crystal X-ray diffraction, it was possible to step-wisely monitor the rather complex three-components guest exchange process involving dimethylformamide (DMF, the pristine solvent) and binary mixtures of the flavoring agents. A picture of the structural evolution of the DMF-to-guest replacement occurring inside the MOF crystal was reached by a detailed single-crystal-to-single-crystal monitoring. The relation of the supramolecular arrangement in the pores with selective guests release was then investigated as a function of time and temperature by static headspace GC-MS analysis.
RESUMEN
PB28, a cyclohexylpiperazine derivative, could be a potential strategy for Covid 19 because in a recent study it has been found more active than hydroxychloroquine without interaction with cardiac proteins. PB28 has been designed, developed, and biologically evaluated in the past decade in our research group. A possible mechanism to explain its surprising anti-COVID-19 activity is suggested..
RESUMEN
In this study, a new regenerative strategy to treat several neurodegenerative diseases is suggested by the use of a multitarget approach induced by our small molecule, MC111. Considering the importance of P-gp and BCRP expression on stem cell differentiation and the involvement of TLR4 on neurodegeneration processes, we investigated the effect of MC111, belonging to our library of P-gp active compounds on: (i) TLR4 signaling; (ii) P-gp and BCRP activity and expression; (iii) neurite sprouting. The observed findings exerted by MC111, open a new scenario for a multitarget and regenerative approach in neurodegenerative diseases encouraging the in vivo evaluation of MC111 as new tool in neuroreparative medicine.
RESUMEN
Formyl peptide receptor2 (FPR2) is a G-protein coupled receptor that plays critical roles in inflammatory reactions. FPR2-specific interaction can be possibly used to facilitate the resolution of pathological inflammatory responses by enhancing endogenous anti-inflammation systems. Starting from our lead agonist 5, we designed new ureidopropanamides derivatives able to activate FPR2 in transfected cells and human neutrophils. The new FPR2 agonists showed good stability towards oxidative metabolism in vitro. Moreover, selected compounds showed anti-inflammatory properties in LPS-stimulated rat primary microglial cells. (S)-3-(4-Cyanophenyl)-N-[[1-(3-chloro-4-fluorophenyl)cyclopropyl]methyl]-2-[3-(4-fluorophenyl)ureido]propanamide ((S)-17) emerged as prospective pharmacological tool to study the effects of FPR2 activation in the central nervous system (CNS) being able to reduce IL-1ß and TNF-α levels in LPS-stimulated microglial cells and showing good permeation rate in hCMEC/D3 cells, an in vitro model of blood brain barrier. These results are very promising and can open new therapeutic perspectives in the treatment of CNS disorders characterized by neuroinflammation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Receptores de Lipoxina/agonistas , Uridina/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Barrera Hematoencefálica/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Enfermedades del Sistema Nervioso Central/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Microglía/efectos de los fármacos , Microglía/metabolismo , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Ratas , Ratas Sprague-Dawley , Receptores de Lipoxina/metabolismo , Relación Estructura-Actividad , Uridina/síntesis química , Uridina/químicaRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests, and activities. Various factors are involved in the etiopathogenesis of ASD, including genetic factors, environmental toxins and stressors, impaired immune responses, mitochondrial dysfunction, and neuroinflammation. The heterogeneity in the phenotype among ASD patients and the complex etiology of the condition have long impeded the advancement of the development of pharmacological therapies. In the recent years, the integration of findings from mouse models to human genetics resulted in considerable progress toward the understanding of ASD pathophysiology. Currently, strategies to treat core symptoms of ASD are directed to correct synaptic dysfunctions, abnormalities in central oxytocin, vasopressin, and serotonin neurotransmission, and neuroinflammation. Here, we present a survey of the studies that have suggested molecular targets for drug development for ASD and the state-of-the-art of medicinal chemistry efforts in related areas.
Asunto(s)
Trastorno del Espectro Autista/tratamiento farmacológico , Psicotrópicos/uso terapéutico , Animales , Agonistas de Aminoácidos Excitadores/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de SeñalRESUMEN
Formyl peptide receptorâ 2 (FPR2) is a G protein coupled receptor belonging to the N-formyl peptide receptor (FPR) family that plays critical roles in peripheral and brain inflammatory responses. FPR2 has been proposed as a target for the development of drugs that could facilitate the resolution of chronic inflammatory reactions by enhancing endogenous anti-inflammation systems. Starting from lead compounds previously identified in our laboratories, we designed a new series of ureidopropanamide derivatives with the goal of converting functional activity from agonism into antagonism and to develop new FPR2 antagonists. Although none of the compounds behaved as antagonists, some of the compounds were able to induce receptor desensitization and, thus, functionally behaved as antagonists. Evaluation of these compounds in an inâ vitro model of neuroinflammation showed that they decreased the production of reactive oxygen species in mouse microglial N9 cells after stimulation with lipopolysaccharide. These FPR2 ligands may protect cells from damage due to inflammation-associated oxidative stress.
Asunto(s)
Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Receptores de Formil Péptido/antagonistas & inhibidores , Receptores de Lipoxina/antagonistas & inhibidores , Animales , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HL-60 , Humanos , Inflamación/metabolismo , Ratones , Estructura Molecular , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/química , Especies Reactivas de Oxígeno/metabolismo , Receptores de Formil Péptido/metabolismo , Receptores de Lipoxina/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Gastrin-releasing peptide receptors (GRP-Rs, also known as bombesin 2 receptors) are overexpressed in a variety of human cancers, including prostate cancer, and therefore they represent a promising target for in vivo imaging of tumors using positron emission tomography (PET). Structural modifications of the non-peptidic GRP-R antagonist PD-176252 ((S)-1a) led to the identification of the fluorinated analog (S)-3-(1H-indol-3-yl)-N-[1-[5-(2-fluoroethoxy)pyridin-2-yl]cyclohexylmethyl]-2-methyl-2-[3-(4-nitrophenyl)ureido]propionamide ((S)-1m) that showed high affinity and antagonistic properties for GRP-R. This antagonist was stable in rat plasma and towards microsomal oxidative metabolism in vitro. (S)-1m was successfully radiolabeled with fluorine-18 through a conventional radiochemistry procedure. [18F](S)-1m showed high affinity and displaceable interaction for GRP-Rs in PC3 cells in vitro.
Asunto(s)
Indoles/farmacología , Compuestos de Fenilurea/farmacología , Radiofármacos/farmacología , Receptores de Bombesina/antagonistas & inhibidores , Triptófano/análogos & derivados , Animales , Línea Celular Tumoral , Estabilidad de Medicamentos , Radioisótopos de Flúor , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacocinética , Ligandos , Microsomas Hepáticos/metabolismo , Oxidación-Reducción , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacocinética , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triptófano/síntesis química , Triptófano/farmacologíaRESUMEN
P-glycoprotein is an ATP-binding cassette transporter involved in drug absorption, distribution and excretion. It pumps a wide range of xenobiotic compounds out of the cells and plays a crucial role in Multi Drug Resistance. Moreover, recent studies have demonstrated that changes in P-gp function and/or expression at the blood brain barrier are implicated in the pathogenesis of neurological disorders such as therapy-refractory epilepsy, Alzheimer's and Parkinson's disease. In the last decades the studies have been addressed to the discovery of potent P-gp inhibitors able to revert pharmacoresistance and to the development of PET tracers to detect P-gp activity and expression for an early diagnosis and therapy monitoring of neurodegenerative disease. However, clinical trials have reported only limited success in reversing MDR and radiolabeled ligands were not actually useful to study differences of transporter function in different brain regions due to their low brain uptake. The difficulties into the discovery of new ligands is due to the use of different experimental assays, to the fact that P-gp is highly flexible protein with different binging sites and available crystallographic structures for the protein have inadequate resolution. To overcome these limitations research groups prefer computational approaches such as homology models in their structure-based design or ligand-based methodologies. A recent approach aimed to identify ligands which can interrupt ATP-binding and hydrolysis by P-gp, by interacting at the NBDs of the protein. In this review results from radiolabeled, substrates and inhibitors, for monitoring the activity and expression of P-gp, respectively, are presented.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Diseño de Fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Humanos , LigandosRESUMEN
Here, we describe the very first attempt to visualize in vivo formyl peptide receptors (FPRs) in mouse brain by positron emission tomography (PET). FPRs are expressed in microglial cells where they mediate chemotactic activity of ß-amyloid peptide in Alzheimer disease and, thus, are involved in neuroinflammatory processes. To this purpose, we have selected (2S)-3-(1H-Indol-3-yl)-2-{[(4-methoxyphenyl)carbamoyl]amino}-N-{[1-(5-methoxypyridin-2-yl)cyclohexyl]methyl}propanamide ((S)-1), that we have previously identified as a potent non-peptidic FPR agonist. (S)-[(11) C]-1 has been prepared in high radiochemical yield. (S)-[(11) C]-1 showed very low penetration of blood-brain barrier and, thus, was unable to accumulate into the brain. In addition, (S)-[(11) C]-1 was not able to label FPRs receptors in brain slices of PS19 and APP23 mice, two animal models of Alzheimer disease. Although (S)-[(11) C]-1 was not suitable to visualize FPRs in the brain, this study provides useful information for the design and characterization of future potential PET radioligands for visualization of brain FPRs by PET.
Asunto(s)
Encéfalo/metabolismo , Modelos Animales de Enfermedad , Indoles/metabolismo , Inflamación/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Tomografía de Emisión de Positrones , Piridinas/metabolismo , Receptores de Formil Péptido/metabolismo , Animales , Encéfalo/patología , Células CACO-2 , Radioisótopos de Carbono , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Inflamación/patología , Ratones , Ratones Transgénicos , Estructura Molecular , Neuronas/metabolismo , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-DawleyRESUMEN
The 5-HT7 serotonin receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 receptors and showed selectivity towards 5-HT6 and dopamine D2 receptors and different selectivity for 5-HT1A and α1 adrenergic receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 receptor in vivo.
Asunto(s)
Piperazinas/química , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacocinética , Animales , Barrera Hematoencefálica/metabolismo , Diseño de Fármacos , Estabilidad de Medicamentos , Ratones , Microsomas/metabolismo , Piperazinas/farmacocinética , Piperazinas/farmacologíaRESUMEN
Starting from our lead compound MC70 displaying high P-glycoprotein (P-gp) inhibition activity but low selectivity, a new class of coumarine derivatives was studied to develop selective and fluorescent P-gp ligands. In this series, the biphenyl moiety of MC70 was replaced with the coumarine fluorophore as a bioisostere of the biphenyl nucleus in order to improve the selectivity toward P-gp and the fluorescent properties for in vitro studies. Moreover, the presence and position of substituents on the coumarine nucleus were probed to develop suitable fluorescent probes to study the expression and activity of P-gp in living cells. The best result was found for compound 4c, which exerts a good P-gp activity profile (EC50 = 13 µM) as substrate and a high selectivity toward the pump since it is inactive toward MRP1.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Compuestos de Bifenilo/química , Cromonas/química , Cumarinas/química , Colorantes Fluorescentes/química , Isoquinolinas/química , Tetrahidroisoquinolinas/química , Animales , Cromonas/síntesis química , Cumarinas/síntesis química , Perros , Colorantes Fluorescentes/síntesis química , Isoquinolinas/síntesis química , Ligandos , Células de Riñón Canino Madin DarbyRESUMEN
G protein-coupled receptors (GPCRs) mediate biological signal transduction through complex molecular pathways. Therapeutic effects of GPCR-directed drugs are typically accompanied by unwanted side effects, owing in part to the parallel engagement of multiple signaling mechanisms. The discovery of drugs that are 'functionally selective' towards therapeutic effects, based on their selective control of cellular responses through a given GPCR, is thus a major goal in pharmacology today. In the present study, we show that several arylpiperazine ligands of the serotonin 5-HT1A receptor (5-HT1AR) preferentially activate 3',5'-cyclic adenosine monophosphate (cAMP) signaling versus ß-arrestin-2 recruitment. The pharmacology of these compounds is thus qualitatively different from the endogenous agonist serotonin, indicating functional selectivity of 5-HT1AR-mediated response pathways. Preliminary evidence suggests that phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) downstream of 5-HT1AR is a substrate of functionally selective signaling by partial agonists. We propose that the compounds described in the present study are useful starting points for the development of signaling pathway-selective drugs targeting 5-HT1AR.
Asunto(s)
Arrestinas/metabolismo , AMP Cíclico/metabolismo , Piperazinas/química , Receptor de Serotonina 5-HT1A/química , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Ligandos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Piperazina , Piperazinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Arrestina beta 2 , beta-ArrestinasRESUMEN
N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists that were designed starting from our lead agonist (S)-3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Several of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds.
Asunto(s)
Amidas/química , Evaluación Preclínica de Medicamentos/métodos , Receptores de Formil Péptido/agonistas , Receptores de Lipoxina/agonistas , Amidas/síntesis química , Animales , Calcio/metabolismo , Técnicas de Química Sintética , Estabilidad de Medicamentos , Células HL-60/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Microsomas Hepáticos/efectos de los fármacos , Activación Neutrófila/efectos de los fármacos , Ratas , Receptores de Formil Péptido/química , Receptores de Lipoxina/química , Especificidad de la Especie , EstereoisomerismoRESUMEN
Generations of modulators of the efflux pump P-glycoprotein (P-gp) have been produced as tools to counteract the Multidrug Resistance (MDR) phenomenon in tumor therapy, but clinical trials were not successful so far. With the aim of contributing to the development of novel P-gp modulators, we started from recently studied high-affinity sigma-2 (σ2) receptor ligands that showed also potent interaction with P-gp. For σ2 receptors high-affinity binding, a basic N-atom is a strict requirement. Therefore, we reduced the basic character of the N-atom present in these ligands, and we obtained potent P-gp modulators with poor or null σ2 receptor affinity. We also evaluated whether modulation of P-gp by these novel compounds involved consumption of ATP (as P-gp substrates do), as a source of energy to support the efflux. Surprisingly, even small structural changes resulted in opposite behavior, with amide 13 depleting ATP, in contrast to its isomer 18. Two compounds, 15 and 25, emerged for their potent activity at P-gp, and deserve further investigations as tools for P-gp modulation.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Receptores sigma/metabolismo , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Adenosina Trifosfato/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Células Cultivadas , Perros , Relación Dosis-Respuesta a Droga , Ligandos , Estructura Molecular , Receptores sigma/química , Relación Estructura-Actividad , Especificidad por Sustrato , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/metabolismoRESUMEN
The development of P-glycoprotein (P-gp) ligands remains of considerable interest, mostly for investigating the protein's structure and transport mechanism. In recent years, many different generations of ligands have been tested for their ability to modulate P-gp activity. The aim of the present work is to perform SAR studies on tetrahydroisoquinoline derivatives in order to design potent and selective P-gp ligands. For this purpose, the effect of bioisosteric replacement and the role of flexibility have been investigated, and four series of tetrahydroisoquinoline ligands have been developed: (a) 2-aryloxazole bioisosteres, (b) elongated analogues, (c) 2H-chromene, and (d) 2-biphenyl derivatives. The results showed that both 2-biphenyl derivative 20b and elongated derivative 6g behaved as strong P-gp substrates. In conclusion, important aspects for developing potent and selective P-gp ligands have been highlighted, providing a solid starting point for further optimization.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Compuestos de Bifenilo/síntesis química , Tetrahidroisoquinolinas/síntesis química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Compuestos de Bifenilo/química , Perros , Fluoresceínas/metabolismo , Ligandos , Células de Riñón Canino Madin Darby , Ratones , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Relación Estructura-Actividad , Tetrahidroisoquinolinas/químicaRESUMEN
One of the principal reasons for the chemotherapy failure is the overexpression of drug efflux pumps, ABCB1 (also known as MDR1 or P-gp) and ABCC1 (also known as MRP1), whose inhibition remains a priority to circumvent drug resistance. We have recently shown a clear trend between lipophilicity and P-glycoprotein inhibitory activity for a class of galloyl-based modulators targeting P-glycoprotein and MRP1. Herein we report a new series of polymethoxy benzamides, whose lipophilicity was modulated through the establishment of an intramolecular hydrogen bond (IMHB) which allows reaching of P-gp inhibitory activity at the submicromolar IC50 level. The present study provides a strong rationale for candidates in the presence of IMHB as a key element for a high P-gp inhibitory activity.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Anilidas/química , Antineoplásicos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Anilidas/síntesis química , Anilidas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Células CACO-2 , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Perros , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Fluoresceínas/metabolismo , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Células de Riñón Canino Madin Darby , Simulación de Dinámica Molecular , Relación Estructura-ActividadRESUMEN
Despite the promising potentials of σ2 receptors in cancer therapy and diagnosis, there are still ambiguities related to the nature and physiological role of the σ2 protein. With the aim of providing potent and reliable tools to be used in σ2 receptor research, we developed a novel series of fluorescent σ2 ligands on the basis of our previous work, where high-affinity σ2 ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (1, PB28) was used as the pharmacophore. Compared to the previous compounds, these novel ligands displayed improved fluorescence and σ2 binding properties, were σ2-specifically taken up by breast tumor cells, and were successfully employed in confocal microscopy. Compound 14, which was the best compromise between pharmacological and fluorescent properties, was successfully employed in flow cytometry, demonstrating its potential to be used as a tool in nonradioactive binding assays for studying the affinity of putative σ2 receptor ligands.
Asunto(s)
Piperazinas/síntesis química , Receptores sigma/metabolismo , Animales , Citometría de Flujo , Fluorescencia , Cobayas , Humanos , Ligandos , Células MCF-7 , Masculino , Piperazinas/metabolismo , RatasRESUMEN
In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [(11)C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [(11)C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands.
Asunto(s)
Piperazinas/síntesis química , Tomografía de Emisión de Positrones , Propanoles/síntesis química , Pirazinas/síntesis química , Radiofármacos , Receptores de Serotonina/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Células CHO , Isótopos de Carbono , Cricetulus , Células HEK293 , Humanos , Cinética , Ligandos , Estructura Molecular , Fenoles/farmacología , Piperazinas/química , Propanoles/química , Pirazinas/química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Sulfonamidas/farmacología , Porcinos , Distribución TisularRESUMEN
We report the synthesis of compounds structurally related to the high-affinity dopamine D4 receptor ligand N-{2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-methoxybenzamide (1e). All compounds were specifically designed as potential PET radioligands for brain D4 receptor visualization, having lipophilicity within a range for brain uptake and weak non-specific binding (0.75
Asunto(s)
Benzamidas , Encéfalo/metabolismo , Diseño de Fármacos , Piperazinas , Tomografía de Emisión de Positrones , Receptores de Dopamina D4/metabolismo , Animales , Benzamidas/síntesis química , Benzamidas/química , Sitios de Unión/efectos de los fármacos , Células CHO , Cricetulus , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Piperazinas/síntesis química , Piperazinas/química , Ratas , Receptores de Dopamina D4/química , Células Tumorales CultivadasRESUMEN
Starting from the previously developed P-gp ligands 1a and 1b (EC50 = 0.25 µM and 0.65 µM, respectively), new arylmethyloxyphenyl derivatives have been synthesized as P-gp modulators in order to investigate: (i) the effect of small electron-donor groups (OMe) (5-11), (ii) the effect of the replacement of methoxy groups with an electron-withdrawal substituent (Cl) on C-ring (13) (iii) the effect induced by the replacement of C-ring with heteroaromatic cycles such as thiophene and pyrimidine (13, 15, 16), (iv) the effect induced by molecular constriction on C ring (14, 17, 18) on P-gp modulating activity. The results demonstrated that P-gp inhibition potency is strongly correlated to the number of methoxy groups in the A-ring whereas the methoxylation of C-ring seems to poorly affect P-gp activity. The best result was found for compound 10 that displays a nanomolar affinity (EC50 = 7.1 nM) towards P-gp pump and, in the meantime lacks of activity against MRP1 pump.