RESUMEN
The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as the presence of electron-releasing or electron-withdrawing groups on the phenyl ring at the 4- and 5-positions of the thiophene ring, were identified as positive allosteric enhancers at the adenosine A1 receptor in binding (saturation, competition and dissociation kinetics) and functional assays. To better understand the positional requirements of substituents on the 2-amino-3-(p-chlorobenzoyl)thiophene core, the corresponding regioisomeric 4-aryl-5-benzylthiophene analogues were synthesized and found to possess reduced allosteric enhancer activity.
Asunto(s)
Agonistas del Receptor de Adenosina A1/química , Agonistas del Receptor de Adenosina A1/farmacología , Receptor de Adenosina A1/metabolismo , Tiofenos/síntesis química , Tiofenos/farmacología , Agonistas del Receptor de Adenosina A1/síntesis química , Regulación Alostérica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
Adenosine is an ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1, A2A, A2B and A3 adenosine receptors (ARs). Allosteric enhancers to A1ARs may represent novel therapeutic agents because they increase the activity of these receptors by mediating a shift to their active form in the A1AR-G protein ternary complex. In this manner, they are able to amplify the action of endogenous adenosine, which is produced in high concentrations under conditions of metabolic stress. A1AR allosteric enhancers could be used as a justifiable alternative to the exogenous agonists that are characterized by receptor desensitization and downregulation. In this review, an analysis of some of the most interesting allosteric modulators of A1ARs has been reported.
Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Regulación Alostérica/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Tiofenos/farmacología , Agonistas del Receptor de Adenosina A1/química , Animales , Humanos , Ligandos , Receptor de Adenosina A1/química , Tiofenos/químicaRESUMEN
Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/historia , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Antagonistas del Receptor de Adenosina A2/química , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Historia del Siglo XX , Humanos , Multimerización de Proteína , Transducción de Señal/efectos de los fármacosRESUMEN
A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, whereas reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l, and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [(3)H]NECA, from the receptor.
Asunto(s)
Agonistas del Receptor de Adenosina A1/síntesis química , Agonistas del Receptor de Adenosina A1/farmacología , Receptor de Adenosina A1/química , Receptor de Adenosina A1/metabolismo , Tiofenos/síntesis química , Tiofenos/farmacología , Agonistas del Receptor de Adenosina A1/química , Regulación Alostérica/efectos de los fármacos , Animales , Células CHO , Técnicas de Química Sintética , Cricetinae , Cricetulus , Humanos , Cinética , Tiofenos/químicaRESUMEN
2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor.
Asunto(s)
Receptor de Adenosina A1/metabolismo , Tiofenos/síntesis química , Tiofenos/metabolismo , Regulación Alostérica , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
Allosteric enhancers for the A1 adenosine receptor represent a novel and unique drug design strategy to augment the response to endogenous adenosine in a site- and event-specific manner. We have previously investigated a detailed structure-activity relationship study around a wide series of 2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophene derivatives as potent allosteric enhancers of the A1 adenosine receptor. In this manuscript we report our investigation on the influence on allosteric enhancer activity of further substitution at the 4-position of the 2-amino-3-(4-chlorobenzoyl)-thiophene system to explore bulk tolerance by replacement of the arylpiperazine moiety with a series of fused indole nuclei corresponding to 1,2,3,4-tetrahydropyrazino[1,2-a]indole, 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, tetrahydro-γ-carboline, tetrahydroisoquinoline, spiro-1,3-benzodioxolepiperidine, aliphatic tertiary amine, N-alkylaniline, aryl ether and aryl thioether templates. The 1,2,3,4-tetrahydropyrazino[1,2-a]indole derivatives 3a-c and 3e were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor. This study also shows that it is possible to obtain a good separation between allosteric enhancement and antagonistic activity at the A1 adenosine receptor.
Asunto(s)
Receptor de Adenosina A1/metabolismo , Tiofenos/farmacología , Regulación Alostérica/efectos de los fármacos , Animales , Células CHO , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
We recently described the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidines as CB2 receptor partial agonists, showing that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. We describe herein the design and synthesis of the 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxamides, structural isomers of our previously reported pyrazolo[3,4-b]pyridines. All of the new compounds showed high affinity and selectivity for the CB2 receptor in the nanomolar range. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series shows stimulatory effects on forskolin-induced cAMP production acting as inverse agonists.
Asunto(s)
Amidas/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis química , Receptor Cannabinoide CB2/metabolismo , Amidas/química , Amidas/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Unión Competitiva , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Agonismo Inverso de Drogas , Humanos , Masculino , Modelos Moleculares , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Recent developments indicate that CB(2) receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB(2) receptor. Very recently, we have identified the oxazinoquinoline carboxamides as a novel class of CB(2) receptor full agonists. In this paper we describe the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives. Some of the reported compounds showed high affinity and potency at the CB(2) receptor while showing only modest affinity for the centrally expressed CB(1) cannabinoid receptor. Moreover, we found that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series show dose-dependent effects on the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists, and inverse agonists.
Asunto(s)
Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptor Cannabinoide CB2/agonistas , Animales , Diseño de Fármacos , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Piridinas/síntesis química , Pirimidinas/síntesis química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
PURPOSE: This study compared the pharmacokinetic profile, and systemic and local absorption of diclofenac, following dermal patch application and oral administration in Yorkshire-Landrace pigs. PATIENTS AND METHODS: Twelve anesthetized, female, Yorkshire-Landrace pigs were randomized to receive either the dermal patch (FLECTOR(®) patch, 10 × 14 cm; Alpharma Pharmaceuticals, a subsidiary of Pfizer Inc, New York, NY) or 50 mg oral diclofenac (Voltaren(®); Novartis, East Hanover, NJ). Tissue (skin area of 2 × 2 cm and underlying muscles approximately 2-3 cm in depth) and blood (10 mL) samples were collected at timed intervals up to 11.5 hours after initial patch application or oral administration. The concentrations of diclofenac in plasma, skin, and muscle samples were analyzed using validated ultra performance liquid chromatography tandem mass spectrometric methods. RESULTS: Peak systemic exposure of diclofenac was very low by dermal application compared with oral administration (maximum concentration [C(max)] values of 3.5 vs 9640 ng/mL, respectively). Absorption of diclofenac into underlying muscles beneath the dermal patch was sustained, and followed apparently zero-order kinetics, with the skin serving as a depot with elevated concentrations of diclofenac. Concentrations of diclofenac in muscles beneath the patch application site were similar to corresponding tissues after oral administration (C(max) values of 879 and 1160 ng/mL, respectively). In contrast to the wide tissue distribution of diclofenac after oral administration, dermal patch application resulted in high concentrations of diclofenac only on the treated skin and immediate tissue underneath the patch. Low concentrations of diclofenac were observed in the skin and muscles collected from untreated areas contralateral to the site of dermal patch application. CONCLUSION: Dermal patch application resulted in low systemic absorption and high tissue penetration of diclofenac compared with oral administration.
RESUMEN
We have recently reported a detailed structure-activity relationship study around a wide series of 2-amino-3-(4-chlorobenzoyl)-4-[(4-arylpiperazin-1-yl)methyl]thiophene derivatives as potent allosteric enhancers of the A(1) adenosine receptor. In the current study, we have continued to explore the potential of these molecules by synthesizing of a novel series of analogues that share a common 2-amino-3-(4-chlorobenzoyl)thiophene nucleus. Modifications were focused on varying the nature and the position of electron-withdrawing or electron-releasing groups on the phenyl of an arylpiperazine moiety attached at the 4-position of the thiophene ring by a methylene chain, combined with the presence of small alkyl groups (methyl or ethyl), bromine, or aryl moieties at the thiophene C-5 position. In this series of compounds, substitution at the 5-position had a fundamental effect on activity, with the 5-aryl group contributing additively to the allosteric enhancer activity. The thiophene C-5 aryl derivatives 4ad, 4ak, and 4al were the most active compounds in binding and functional experiments.
Asunto(s)
Receptor de Adenosina A1/efectos de los fármacos , Tiofenos/síntesis química , Tiofenos/farmacología , Regulación Alostérica , Humanos , Espectroscopía de Resonancia Magnética , Receptor de Adenosina A1/metabolismo , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB(2) receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20, hCB(2)K(i) = 2.5 nM, SI = 166; 21, hCB(2)K(i) = 0.81 nM, SI = 383; 38, hCB(2)K(i) = 15.8 nM, SI > 633; 56, hCB(2)K(i) = 8.12 nM, SI > 1231; (R)-58, hCB(2)K(i) = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated, and it was found that the (R)-enantiomers exhibited greater affinity at the CB(2) receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB(2) receptor.
Asunto(s)
Quinolinas/metabolismo , Quinolinas/farmacología , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Quinolinas/síntesis química , Quinolinas/química , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Especificidad por SustratoRESUMEN
A relevant problem of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C(5) position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K(i)(hA(3)) = 9.7 nM, IC(50)(hA(3)) = 30 nM, K(i)(hA(1)/hA(3)) = 351, K(i)(hA(2A)/hA(3)) > 515, IC(50)(hA(2B)) > 5 µM) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.
Asunto(s)
Antagonistas del Receptor de Adenosina A3/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Receptor de Adenosina A3/metabolismo , Urea/análogos & derivados , Antagonistas del Receptor de Adenosina A3/química , Antagonistas del Receptor de Adenosina A3/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Modelos Moleculares , Ensayo de Unión Radioligante , Solubilidad , Urea/síntesis química , Urea/química , Urea/farmacología , AguaRESUMEN
In a preliminary article, we reported the potent allosteric enhancer activity at the A(1) adenosine receptor of a small series of 2-amino-3-(4-chlorobenzoyl)-4-[4-(aryl)piperazin-1-yl)methyl]thiophene derivatives bearing electron-withdrawing or electron-releasing groups at the para-position of the phenylpiperazine moiety. In the present study, we report the development of the compounds previously studied by modifying both the number and position of substituents on the phenylpiperazine moiety, aimed at establishing a structure-activity relationship identifying additional compounds with improved activity. The nature and the position of substituents on the phenyl ring tethered to the piperazine seemed to exert a fundamental influence on the allosteric enhancer activity, with the 3,4-difluoro 4i, 3-chloro-4-fluoro 4o, and 4-trifluoromethoxy 4ak derivatives being the most active compounds in binding (saturation and competition experiments) and functional cAMP studies. This study shows that it is also possible to obtain a good separation between allosteric enhancement and antagonistic activity at the A(1) adenosine receptor.
Asunto(s)
Antagonistas del Receptor de Adenosina A1/química , Piperazinas/química , Receptor de Adenosina A1/química , Tiofenos/química , Antagonistas del Receptor de Adenosina A1/síntesis química , Antagonistas del Receptor de Adenosina A1/farmacología , Regulación Alostérica , Animales , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Humanos , Unión Proteica/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A(2A) and A(3) adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the preparation of pyrrolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives which can be considered as 7-deaza analogues of the parent PTPs. We also synthesised a novel series of pyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the reference compounds. In both cases we obtained some examples of potent antagonists (K(i) in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C(5)-, N(8)- and/or N(9)-positions. The pyrrolo-triazolo-pyrimidine derivative 9b appeared to be a potent A(3) adenosine receptor antagonist (K(i)=10 nM) with good selectivity over hA(1) (74-fold) and hA(2A) (20-fold) adenosine receptors combined with low activity at the hA(2B) subtype (IC(50)=906 nM). Moreover, some examples of high-affinity A(1)/A(2A) dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors.
Asunto(s)
Antagonistas de Receptores Purinérgicos P1/química , Pirazoles/química , Pirimidinas/química , Triazoles/química , Humanos , Unión Proteica/efectos de los fármacos , Antagonistas de Receptores Purinérgicos P1/síntesis química , Antagonistas de Receptores Purinérgicos P1/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor de Adenosina A2A/química , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A3/química , Receptor de Adenosina A3/metabolismo , Relación Estructura-ActividadRESUMEN
Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A(2B) adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A(2B) adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A(2B)AR, a new series of compounds was synthesized and evaluated in binding studies against the human A(1), A(2A), A(3), and A(2B)ARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A(2B) receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: K(i) A(2B) = 9.4 nM, IC(50) hA(2B) = 26 nM hA(1)/hA(2B) = 269, hA(2A)/hA(2B) > 106, hA(3)/hA(2B) >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A(2B)AR with good selectivity over AR subtypes (K(i) = 4.0 nM, IC(50) hA(2B) = 20 nM hA(1)/hA(2B) = 183, hA(2A),hA(3)/hA(2B) > 250).
Asunto(s)
Antagonistas del Receptor de Adenosina A2/síntesis química , Bencimidazoles/síntesis química , Modelos Moleculares , Pirazoles/síntesis química , Relación Estructura-Actividad Cuantitativa , Receptor de Adenosina A2B/metabolismo , Xantinas/síntesis química , Antagonistas del Receptor de Adenosina A2/química , Antagonistas del Receptor de Adenosina A2/farmacología , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Unión Competitiva , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Humanos , Pirazoles/química , Pirazoles/farmacología , Ensayo de Unión Radioligante , Xantinas/química , Xantinas/farmacologíaRESUMEN
A series of 4-allyl/benzyl-7,8-dihydro-8-methyl/ethyl-2-[(substituted)isoxazol/pyrazol-3/5-yl]-1H-imidazo[2,1-i]purin-5(4H)-ones has been synthesized and evaluated in radioligand binding assays to determine their affinities at the human A(1), A(2A), and A(3) adenosine receptors. Efficacy at the hA(2B) AR and antagonism of selected ligands at the hA(3) AR were also assessed through cAMP experiments. All of the synthesized molecules exhibited high affinity at the hA(3) AR (K(i) values ranging from 1.46 to 44.8 nM), as well as remarkable selectivity versus A(1), A(2A), and A(2B) AR subtypes. Compound (R)-4-allyl-8-ethyl-7,8-dihydro-2-(3-methoxy-1-methyl-1H-pyrazol-5-yl)-1H-imidazo[2,1-i]purin-5(4H)-one (R-33) was found to be the most potent and selective ligand of the series (K(i) hA(3) = 1.46 nM, K(i) hA(2A)/K(i) hA(3) > 3425; IC(50) hA(2B)/K(i) hA(3) > 3425; K(i) hA(1)/K(i) hA(3) = 1729). Molecular modeling studies were helpful in rationalizing the available structure-activity relationships along with the selectivity profiles of the new series of ligands.
Asunto(s)
Antagonistas del Receptor de Adenosina A3/síntesis química , Purinas/síntesis química , Receptor de Adenosina A3/metabolismo , Antagonistas del Receptor de Adenosina A3/química , Antagonistas del Receptor de Adenosina A3/farmacología , Secuencia de Aminoácidos , Animales , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Purinas/química , Purinas/farmacología , Ensayo de Unión Radioligante , Receptor de Adenosina A2B/genética , Receptor de Adenosina A2B/metabolismo , Receptor de Adenosina A3/química , Receptor de Adenosina A3/genética , Alineación de Secuencia , Estereoisomerismo , Relación Estructura-Actividad , TransfecciónRESUMEN
The synthesis and evaluation of a series of 2-amino-3-(4-chlorobenzoyl)-4-[4-(alkyl/aryl)piperazin-yl]thiophene derivatives as allosteric enhancers of the A 1-adenosine receptor are described. The nature of substituents on the phenyl ring tethered to the piperazine seem to exert a fundamental influence on the allosteric enhancer activity, with the 4-chlorophenyl 8f and 4-trifluoromethyl 8j derivatives being the most active compounds in binding (saturation and displacement experiments) and functional cAMP studies.
Asunto(s)
Agonistas del Receptor de Adenosina A1 , Tiofenos/síntesis química , Tiofenos/farmacología , Regulación Alostérica , Animales , Células CHO , Cricetinae , CricetulusRESUMEN
A new series of 1,3-dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives has been identified as potent A(2B) adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A(2B), A(1), A(2A), and A(3) adenosine receptors. N-(4-chloro-phenyl)-2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl] (11c) showed a high affinity for the human A(2B) adenosine receptor K(i)=7nM and good selectivity (A(1), A(2A), A(3)/A(2B)>140). Synthesis and SAR of this novel class of compounds is presented herein.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Pirazoles/síntesis química , Pirazoles/farmacología , Receptor de Adenosina A2B/metabolismo , Xantinas/síntesis química , Xantinas/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Pirazoles/química , Relación Estructura-Actividad , Xantinas/químicaRESUMEN
The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack of specific and subtype-selective antagonists with a "druglike" profile. However, a tyrosine derivative named KN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplification of KN-62, the present study was designed to evaluate the functional antagonistic properties of a novel series of glycine derivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonistic activity of these glycine derivatives was tested on HEK293 cells transfected with the human P2X7 receptor. The most potent P2X7 receptor antagonist identified in this study (compound 4g) contains an o-fluorine substituent on the phenylpiperazine moiety and had an IC50 of 12.1 nM. The biological responses investigated were ATP-dependent Ca2+ influx across the plasma membrane and ethidium bromide uptake.
Asunto(s)
Glicina/análogos & derivados , Glicina/síntesis química , Isoquinolinas/síntesis química , Antagonistas del Receptor Purinérgico P2 , Sulfonamidas/síntesis química , Tirosina/química , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/química , Adenosina Trifosfato/metabolismo , Calcio/metabolismo , Línea Celular , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular , Etidio/metabolismo , Colorantes Fluorescentes/metabolismo , Glicina/farmacología , Humanos , Isoquinolinas/farmacología , Naftalenos/síntesis química , Naftalenos/farmacología , Receptores Purinérgicos P2X7 , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-Actividad , Sulfonamidas/farmacología , Sulfonas/síntesis química , Sulfonas/farmacología , beta-Alanina/análogos & derivados , beta-Alanina/síntesis química , beta-Alanina/farmacologíaRESUMEN
Allosteric enhancers at the adenosine A(1) receptor have received attention as anti-arrhythmic cardiac agents, and, more recently, as anti-lipolytic agents. In addition, allosteric modulators at the adenosine A(1) receptor have therapeutic potential as analgesics and neuroprotective agents. In particular, the compounds with improved potency as enhancers and reduced antagonist properties are mentioned.