RESUMEN
5-HT(1A) receptor and α(1)-adrenoreceptor (α(1)-AR) binding sites recognized by the 1,4-dioxanes 2-4 display reversed stereochemical requirements. (S)-2 proved to be a potent 5-HT(1A) receptor agonist highly selective over α(1)-AR subtypes. Chirality influenced the anticancer activity of 3 and 4 in human prostate cancer cells (PC-3): (R)-4, eutomer at the α(1d)-AR subtype, was the most potent. The decreased effect of 4 and (R)-4 in α(1d)-AR silenced PC-3 cells confirmed that their anticancer activity was α(1d)-AR-dependent.
Asunto(s)
Dioxanos/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores de Serotonina 5-HT1/efectos de los fármacos , Sitios de Unión , Línea Celular , Dioxanos/química , Humanos , Espectroscopía de Resonancia Magnética , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Serotonina 5-HT1/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of novel openphendioxan analogues were synthesized and tested at α(1)-adrenoreceptor (AR) subtypes by binding and functional assays. The α(1d)-AR binding profile was also examined by means of 2D, 3D-QSAR together with docking studies. Multiple regression analysis suggested the relevance of adequate number of heteroatoms in the whole molecule and of passive membrane diffusion to enhance α(1d)-AR affinity. Docking simulations against a computational structural model of the biological target further proved this evidence and furnished support for chemiometric analysis, where polar, electrostatic, hydrophobic and shape effects of the ortho substituents in the phenoxy terminal, most likely governing ligand binding, helped the depiction of pharmacophore hypothesis for the examined ligands data set.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Dioxanos/química , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/síntesis química , Animales , Sitios de Unión , Biología Computacional , Simulación por Computador , Dioxanos/farmacología , Ligandos , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Wistar , Análisis de Regresión , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Novel 1,4-dioxane compounds structurally related to WB 4101 (1) were prepared in order to investigate the possibility that the quite planar 1,4-benzodioxane template of 1 might be replaced by the less conformationally constrained 1,4-dioxane ring. The biological profiles of the new compounds were assessed using binding assays at human cloned alpha 1-adrenoreceptor (alpha 1-AR) subtypes and 5-HT 1A receptors, expressed in Chinese hamster ovary and HeLa cell membranes, respectively, and by functional experiments in isolated rat vas deferens (alpha 1A), spleen (alpha 1B), and aorta (alpha 1D). Moreover, the cytotoxic effects of the novel compounds were determined in PC-3 prostate cancer cells. The results showed that the properly substituted 1,4-dioxane nucleus proved to be a suitable scaffold for selective alpha 1D-AR antagonists (compound 14), potential anticancer agents (compound 13), and full 5-HT 1A receptor agonists (compound 15). In particular, compound 15 may represent a novel lead in the development of highly potent 5-HT 1A receptor full agonists useful as antidepressant and neuroprotective agents.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Benceno/química , Dioxanos/química , Dioxanos/farmacología , Etilaminas/química , Etilaminas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Modelos Moleculares , Estructura Molecular , Receptores Adrenérgicos alfa 1/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To investigate the role of Group I metabotropic glutamate (mGlu) receptor subtypes on reflex-induced micturition in anaesthetized and conscious rats using selective mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) allosteric antagonists. MATERIALS AND METHODS: The affinity of the compounds at mGlu1 and mGlu5 receptor subtypes was evaluated by displacement of tritiated R214127 and MPEP, respectively, from rat brain tissue. Effects of intravenous (i.v.) administration of the compounds on isovolumic bladder contractions were evaluated in anaesthetized rats. Effects of MPEP and NPS 2407 on bladder filling and voiding were evaluated by cystometry using saline or diluted (0.2%) acetic acid (MPEP only) infusion of bladders in conscious rats. RESULTS: Binding studies confirmed the selectivity of the mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) compounds. Isovolumic bladder contractions were blocked after i.v. administration of all compounds. However, the mGlu5 antagonists were generally more potent than mGlu1 antagonists. In conscious rats with bladders infused with saline, MPEP dose-dependently and significantly increased bladder capacity starting from oral administration of 10 mg/kg. Oral administration of NPS 2407 (up to 30 mg/kg) did not induce consistent changes in bladder capacity or micturition pressure. MPEP (10 mg/kg, orally) was also evaluated in conscious rats with bladders infused with diluted acetic acid. In this model, MPEP reduced bladder instability counteracting the decrease of bladder volume capacity induced by acetic acid. There were no consistent effects on bladder contractility. CONCLUSIONS: The results indicate that i.v. and oral administration of selective mGlu5 antagonists, but not those selective for the mGlu1 subtype, have a marked inhibitory effect on reflex micturition pathways in the rat.
Asunto(s)
Contracción Muscular/efectos de los fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Vejiga Urinaria/fisiología , Micción/efectos de los fármacos , Urodinámica/fisiología , Animales , Femenino , Masculino , Contracción Muscular/fisiología , Piranos/química , Piranos/farmacología , Piridinas/química , Piridinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Tiazoles/química , Tiazoles/farmacología , Micción/fisiologíaRESUMEN
alpha(1)-Adrenoceptor selective antagonists are crucial in investigating the role and biological functions of alpha(1)-adrenoceptor subtypes. We synthesized and studied the alpha(1)-adrenoceptor blocking properties of new molecules structurally related to the alpha(1B)-adrenoceptor selective antagonist (+)-cyclazosin, in an attempt to improve its receptor selectivity. In particular, we investigated the importance of substituents introduced at position 5 of the 2-furan moiety of (+)-cyclazosin and its replacement with classical isosteric rings. The 5-methylfuryl derivative (+)-3, [(+)-metcyclazosin], improved the pharmacological properties of the progenitor, displaying a competitive antagonism and an 11 fold increased selectivity for alpha(1B) over alpha(1A), while maintaining a similar selectivity for the alpha(1B)-adrenoceptor relative to the alpha(1D)-adrenoceptor. Compound (+)-3 may represent a useful tool for alpha(1B)-adrenoceptor characterization in functional studies.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Furanos/química , Prazosina/química , Quinazolinas/síntesis química , Quinoxalinas/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Aorta/efectos de los fármacos , Unión Competitiva , Masculino , Estructura Molecular , Quinazolinas/química , Quinazolinas/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/metabolismo , Bazo/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the role of cyclooxygenase (COX) isozymes (COX-1 and -2) in the regulation of bladder volume capacity (BVC) in several rat urodynamic models, using a selection of nonsteroidal anti-inflammatory drugs (NSAIDs), some selective for COX-2, correlating the potency of the tested compounds in the urodynamic models and their in vitro potency as inhibitors of COX isozymes, to verify the relative importance of the different isozymes. MATERIALS AND METHODS: The effects of an i.v. administration of several nonselective and selective COX-2 inhibitors (indomethacin, meloxicam, naproxen, aspirin, paracetamol, flurbiprofen, nimesulide, NS-398, celecoxib, rofecoxib and L 745337) on bladder filling and voiding were evaluated in conscious and anaesthetized rats by cystometry. The cystometry was done in conscious rats 1 day after catheter implantation, by filling the bladder with dilute acetic acid (0.2%) or saline, and again with saline 5 days after catheterization. Effects on isovolumic bladder contractions in anaesthetized rats were also evaluated. RESULTS: All the NSAIDs tested dose-dependently increased BVC; their potency at increasing BVC during infusion of the bladder with acetic acid was similar to that evaluated with saline on cystometry 1 day after catheterization. When a nonselective (naproxen) and a selective (nimesulide) COX-2 inhibitor were tested in rats with bladders infused with saline 5 days after catheterization, their effects on BVC were significantly lower than those evaluated at 1 day. All tested compounds dose-dependently inhibited isovolumic bladder contractions in anaesthetized rats. There was a good correlation between the potency in inhibiting the isovolumic bladder contractions in anaesthetized rats and in increasing BVC during cystometry in conscious rats with the bladder infused with acetic acid. The potency of the compounds in the cystometry model with bladders infused with acetic and in the isovolumic bladder voiding contractions correlated well with COX-2 inhibition, but not COX-1. CONCLUSIONS: Both nonselective and COX-2 selective inhibitors are more active in inhibiting the micturition reflex in rats with bladder overactivity caused by bladder irritation than in normal rats. The potency of the anti-inflammatory compounds in inhibiting bladder overactivity induced by chemical or surgical irritation, and their activity in a cystometrographic model practically independent of bladder irritation (isovolumic bladder contractions in anaesthetized rats), was related to the potency as inhibitors of COX-2 isozyme. This suggests that the involvement of prostaglandins in the micturition reflex in rats is mainly mediated by this isozyme.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Vejiga Urinaria/efectos de los fármacos , Micción/efectos de los fármacos , Urodinámica/efectos de los fármacos , Animales , Femenino , Isoenzimas/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Reflejo/fisiología , Micción/fisiologíaRESUMEN
A series of new alpha1-adrenoreceptor antagonists (5-18) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue 4 ("openphendioxan"). All the compounds synthesized were potent antagonists and generally displayed, similarly to 4, the highest affinity values at alpha1D- with respect to alpha1A- and alpha1B-AR subtypes and 5-HT1A subtype. By sulforhodamine B (SRB) assay on human PC-3 prostate cancer cells, the new compounds showed antitumor activity (estimated on the basis of three parameters GI50, TGI, LC50), at low micromolar concentration, with 7 ("clopenphendioxan") exhibiting the highest efficacy. Moreover, this study highlighted for the first time alpha1D- and alpha1B-AR expression in PC3 cells and also demonstrated the involvement of these subtypes in the modulation of apoptosis and cell proliferation. A significant reduction of alpha1D- and alpha1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Antineoplásicos/síntesis química , Apoptosis , Proliferación Celular , Éteres Fenílicos/síntesis química , Neoplasias de la Próstata/patología , Receptores Adrenérgicos alfa 1/fisiología , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Células CHO , Línea Celular Tumoral , Cricetinae , Cricetulus , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
BACKGROUND: Antimuscarinic agents are the most popular treatment for overactive bladder and their efficacy in man is well documented, producing decreased urinary frequency and an increase in bladder capacity. During cystometry in rats, however, the main effect reported after acute treatment with antimuscarinics is a decrease in peak micturition pressure together with little or no effect on bladder capacity. In the present experiments we studied the effects, in rats, of the two most widely used antimuscarinic drugs, namely oxybutynin and tolterodine, utilising several different cystometrographic conditions. The aim was to determine the experimental conditions required to reproduce the clinical pharmacological effects of antimuscarinic agents, as seen in humans, in particular their ability to increase bladder capacity. RESULTS: Intravenous or oral administration of tolterodine or oxybutynin in conscious rats utilized 1 day after catheter implantation and with saline infusion at constant rate of 0.1 ml/min, gave a dose-dependent decrease of micturition pressure (MP) with no significant change in bladder volume capacity (BVC). When the saline infusion rate into the bladder was decreased to 0.025 ml/min, the effect of oral oxybutynin was similar to that obtained with the higher infusion rate. Also, experiments were performed in rats in which bladders were infused with suramin (3 and 10 microM) in order to block the non-adrenergic, non-cholinergic component of bladder contraction. Under these conditions, oral administration of oxybutynin significantly reduced MP (as observed previously), but again BVC was not significantly changed. In conscious rats with bladders infused with diluted acetic acid, both tolterodine and oxybutynin administered at the same doses as in animals infused with saline, reduced MP, although the reduction appeared less marked, with no effect on BVC. In conscious rats utilized 5 days after catheter implantation, a situation where inflammation due to surgery is reduced, the effect of tolterodine (i.v.) and oxybutynin (p.o.) on MP was smaller and similar, respectively, to that observed in rats utilized 1 day after catheter implantation, but the increase of BVC was not statistically significant. In anesthetized rats, i.v. administration of oxybutynin again induced a significant decrease in MP, although it was of questionable relevance. Both BVC and threshold pressure were not significantly reduced. The number and amplitude of high frequency oscillations in MP were unmodified by treatment. Finally, in conscious obstructed rats, intravenous oxybutynin did not modify frequency and amplitude of non-voiding contractions or bladder capacity and micturition volume. CONCLUSION: Despite the different experimental conditions used, the only effect on cystometrographic parameters of oxybutynin and tolterodine in anesthetized and conscious rats was a decrease in MP, whereas BVC was hardly and non-significantly affected. Therefore, it is difficult to reproduce in rats the cystometrographic increase in BVC as observed in humans after chronic administration of antimuscarinic agents, whereas the acute effects seem more similar.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Cresoles/farmacología , Ácidos Mandélicos/farmacología , Antagonistas Muscarínicos/farmacología , Fenilpropanolamina/farmacología , Vejiga Urinaria/efectos de los fármacos , Micción/efectos de los fármacos , Animales , Masculino , Ratas , Tartrato de Tolterodina , Cateterismo Urinario , Incontinencia Urinaria/tratamiento farmacológicoRESUMEN
Based on a pharmacophore alignment on known non-competitive mGluR5 inhibitors applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)'s as low as around 100 nM were achieved.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Antagonistas de Aminoácidos Excitadores/química , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
A series of new 1,2,4-benzothiadiazine derivatives with an arylpiperazine mojety linked at position 3 of the heterocyclic ring were synthesized and assessed for their pharmacological profiles at alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) by functional experiments and by in vitro binding studies at human cloned 5-HT(1A) receptor. Compound 1 was identified as a novel alpha(1D) antagonist (pK(b)alpha(1D)=7.59; alpha(1D)/alpha(1A)>389; alpha(1D)/alpha(1B)=135) with high selectivity over 5-HT(1A) receptor (5-HT(1A)/alpha(1D)<0.01), while compound 6, a 3,4-dihydro-derivative, was characterized as a novel 5-HT(1A) receptor ligand, highly selective over alpha(1D)-adrenoceptor subtype (pK(i)5-HT(1A)=8.04; 5-HT(1A)/alpha(1D)=1096). Further pharmacological studies demonstrated that 6 is a partial agonist at 5-HT(1A) receptor (E(max)=23, pD(2)=6.92).
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Benzotiadiazinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT1 , Animales , Aorta Torácica , Benzotiadiazinas/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Técnicas In Vitro , Ligandos , Masculino , Ratas , Receptores Adrenérgicos alfa 1/metabolismo , Bazo , Relación Estructura-Actividad , Conducto DeferenteRESUMEN
To combine in the same molecule alpha(1)-adrenoreceptor blocking and antioxidant properties, compounds 2-5 were designed and synthesized. All compounds were effective alpha(1)-adrenoreceptor antagonists and were tested in both functional and binding assays. In addition, compounds 2 and 5 also displayed significant capacity to inhibit intracellular oxidative stress, whereas 3-5 exerted potent antiproliferative activity in lymph node carcinoma of prostate cells.
Asunto(s)
Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Prazosina/análogos & derivados , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Animales , Antioxidantes/síntesis química , Bioquímica/métodos , Células CHO , Carcinoma/tratamiento farmacológico , Cricetinae , Cricetulus , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Técnicas In Vitro , Masculino , Prazosina/química , Neoplasias de la Próstata/tratamiento farmacológico , Ratas , Especies Reactivas de Oxígeno , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Relación Estructura-Actividad , Ácido Tióctico/química , Ácido Tióctico/farmacología , Células Tumorales Cultivadas , Conducto Deferente/efectos de los fármacosRESUMEN
In the attempt to define more accurately structure-affinity relationships for sigma(1) and sigma(2) ligands, we synthesized and tested on sigma subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine, in which the effect of modifications on the aralkyl moiety was studied in a systematic way. The affinity of the compounds here described varied to a great extent, with a sigma(2)/sigma(1) selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative to bind to sigma(1) receptors in a different way than piperidines, we synthesized and tested a series of piperazine compounds; the comparison of their affinity with that of the corresponding piperidines strongly supports the possibility of a different binding mode. While the compounds here described are on the whole selective for sigma vs serotonin 5-HT(1A) and dopamine D(2) receptors, 9aa, 9ba and 9ab possess a remarkable affinity for both sigma and 5-HT(1A) receptors, with K(i) in the nanomolar range, and are selective with respect to D(2) receptors. They displayed also a partial agonist profile in a human 5-HT(1A) [(35)S]GTP gamma S binding assay, suggesting their potential use as atypical antipsychotic agents.
Asunto(s)
Receptores sigma/agonistas , Relación Estructura-Actividad , Animales , Sitios de Unión , Bioquímica/métodos , Células Cultivadas , Evaluación Preclínica de Medicamentos , Cobayas , Humanos , Concentración 50 Inhibidora , Ligandos , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacología , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores Opioides/agonistas , Receptores Opioides/efectos de los fármacos , Receptores Opioides/genética , Receptores sigma/efectos de los fármacos , Receptores sigma/metabolismo , Agonistas del Receptor de Serotonina 5-HT1 , Receptor Sigma-1RESUMEN
Plaque rupture and thromboembolism play a major role in atherosclerotic acute syndrome. Experimental studies have demonstrated the potential direct anti-atherosclerotic effects of calcium antagonists. We investigated the in vitro effect of lercanidipine (REC 15/2375), a third-generation, highly lipophilic calcium antagonist on cholesterol metabolism and matrix metalloproteinases secretion in macrophages, two functions that predispose plaques to rupture. Lercanidipine (10(-6)-10(-5) M) inhibited cholesterol esterification in macrophages and reduced cellular free and esterified cholesterol accumulation from acetylated LDL (63%, 62% of control P < 0.05, respectively). In addition, lercanidipine inhibited the release of metalloproteinases in the extracellular medium (50% and 95% inhibition at 10(-5) M for MMP-9 and MMP-2, respectively). Experiments performed with lercanidipine enantiomers or other dihydropyridine derivatives, endowed with different lipophilicity and affinity for calcium channels, indicated that the above effects could be related to the lipophilic, but not to the calcium channel blocking properties of these molecules. When cells, after exposure to the drug, were allowed to equilibrate, lercanidipine inhibitory action could be observed at initial concentrations as low as 10(-9) M, which is the actual concentration range observed in plasma in clinical settings. In conclusion, our data indicate that lercanidipine may exert potent anti-atherosclerotic effects by inhibiting macrophage functions involved in plaque stability.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Colesterol/metabolismo , Dihidropiridinas/farmacología , Macrófagos Peritoneales/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Animales , Células Cultivadas , Ésteres del Colesterol/metabolismo , Electroforesis en Gel de Poliacrilamida , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Monocitos/metabolismo , Especificidad de la EspecieRESUMEN
In the present study, more than 75 compounds structurally related to BMY 7378 have been designed and synthesized. Structural variations of each part of the reference molecule have been introduced, obtaining highly selective ligands for the alpha(1d) adrenergic receptor. The molecular determinants for selectivity at this receptor are essentially held by the phenyl substituent in the phenylpiperazine moiety. The integration of an extensive SAR analysis with docking simulations using the rhodopsin-based models of the three alpha(1)-AR subtypes and of the 5-HT(1A) receptor provides significant insights into the characterization of the receptor binding sites as well as into the molecular determinants of ligand selectivity at the alpha(1d)-AR and the 5-HT(1A) receptors. The results of multiple copies simultaneous search (MCSS) on the substituted phenylpiperazines together with those of manual docking of compounds BMY 7378 and 69 into the putative binding sites of the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR, and the 5-HT(1A) receptors suggest that the phenylpiperazine moiety would dock into a site formed by amino acids in helices 3, 4, 5, 6 and extracellular loop 2 (E2), whereas the spirocyclic ring of the ligand docks into a site formed by amino acids of helices 1, 2, 3, and 7. This docking mode is consistent with the SAR data produced in this work. Furthermore, the binding site of the imide moiety does not allow for the simultaneous involvement of the two carbonyl oxygen atoms in H-bonding interactions, consistent with the SAR data, in particular with the results obtained with the lactam derivative 128. The results of docking simulations also suggest that the second and third extracellular loops may act as selectivity filters for the substituted phenylpiperazines. The most potent and selective compounds for alpha(1d) adrenergic receptor, i.e., 69 (Rec 26D/038) and 128 (Rec 26D/073), are characterized by the presence of the 2,5-dichlorophenylpiperazine moiety.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Imidas/síntesis química , Compuestos de Espiro/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Secuencia de Aminoácidos , Animales , Sitios de Unión , Células CHO , Cricetinae , Cobayas , Células HeLa , Humanos , Imidas/química , Imidas/farmacología , Técnicas In Vitro , Ligandos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Estructura Terciaria de Proteína , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/metabolismo , Alineación de Secuencia , Antagonistas del Receptor de Serotonina 5-HT1 , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
In a search for structurally new alpha(1)-adrenoreceptor (alpha(1)-AR) antagonists, prazosin (1)-related compounds 2-11 were synthesized and their affinity profiles were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO cells expressing human cloned alpha(1)-AR subtypes. Transformation of the piperazinylquinazoline moiety of 1 into an aminomethyltetrahydroacridine system afforded compound 2, endowed with reduced affinity, in particular for the alpha(1A)-AR subtype. Then, to investigate the optimal features of the tricyclic moiety, the aliphatic ring of 2 was modified by synthesizing the lower and higher homologues 3 and 4. An analysis of the pharmacological profile, together with a molecular modeling study, indicated the tetrahydroacridine moiety as the most promising skeleton for alpha(1)-antagonism. Compounds 5-8, where the replacement of the furoyl group of 2 with a benzoyl moiety afforded the possibility to evaluate the effect of the substituent trifluoromethyl on receptor binding, resulted, except for 7, in a rather surprising selectivity toward alpha(1B)-AR, in particular vs the alpha(1A) subtype. Also the insertion of the 2,6-dimethoxyphenoxyethyl function of WB 4101 on the tetrahydroacridine skeleton of 2, and/or the replacement of the aromatic amino function with a hydroxy group, affording derivatives 9-11, resulted in alpha(1B)-AR selectivity also vs the alpha(1D) subtype. On the basis of these results, the tetrahydroacridine moiety emerged as a promising tool for the characterization of the alpha(1)-AR, owing to the receptor subtype selectivity achieved by an appropriate modification of the lateral substituents.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Aminoacridinas/síntesis química , Piperazinas/química , Prazosina/química , Receptores Adrenérgicos alfa 1/metabolismo , Acetilcolinesterasa/química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Aminoacridinas/química , Aminoacridinas/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Células CHO , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Cricetinae , Dioxanos/farmacología , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformación Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Prazosina/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Bazo/efectos de los fármacos , Bazo/fisiología , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
A recent uroselective alpha(1)-adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor alpha(1)-antagonists. All the compounds studied proved to be potent and selective ligands of human cloned alpha(1a)-receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their alpha(1A)-antagonist and their NO-donor properties.
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Cromonas/síntesis química , Donantes de Óxido Nítrico/síntesis química , Ácido Nitroso/química , Oxadiazoles/síntesis química , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Unión Competitiva , Células CHO , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cromonas/química , Cromonas/farmacología , Cricetinae , Células HeLa , Humanos , Técnicas In Vitro , Masculino , Relajación Muscular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Oxadiazoles/química , Oxadiazoles/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
1,3-Dioxolane-based compounds (2-14) were synthesized, and the pharmacological profiles at alpha(1)-adrenoceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)). Compound 9, with a pA(2) of 7.53, 7.36, and 8.65 at alpha(1A), alpha(1B), and alpha(1D), respectively, is the most potent antagonist of the series, while compound 10 with a pA(2) of 8.37 at alpha(1D) subtype and selectivity ratios of 162 (alpha(1D)/alpha(1A)) and 324 (alpha(1D)/alpha(1B)) is the most selective. Binding assays in CHO cell membranes expressing human cloned alpha(1)-adrenoceptor subtypes confirm the pharmacological profiles derived from functional experiments, although the selectivity values are somewhat lower. Therefore, it is concluded that 1,3-dioxolane-based ligands are a new class of alpha(1)-adrenoceptor antagonists.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Dioxolanos/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas de Receptores Adrenérgicos beta 1 , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Células CHO , Cricetinae , Dioxolanos/química , Dioxolanos/farmacología , Humanos , Técnicas In Vitro , Ligandos , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Bazo/efectos de los fármacos , Bazo/fisiología , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
AIM: Lercanidipine is a new vasoselective dihydropyridine calcium channel blocker with a short plasma half-life, long duration of action, and demonstrated cardioprotective properties. We hypothesized that it might be effective at attenuating the adverse impact observed on the coronary compartment and myocardium in the transition phase to heart failure in the UM-X7.1 cardiomyopathic (CM) hamster. METHODS: The effects of 4-month exposure to lercanidipine 3 and 10 mg/kg (daily oral administration) were evaluated in 150-day-old CM hamsters and in age-matched normal hamsters. Coronary reactivity (reactive hyperemia to 30-s coronary occlusion) and the response to the administration of acetylcholine (100 nmol/L) and sodium nitroprusside (1 micromol/L) were assessed monthly, using the isolated perfused heart model. The left ventricular chamber dilatation index and wall thickness, myocardial fibrosis and myocardial capillary density (papillary muscle) were estimated in selected subgroups at monthly intervals. RESULTS: High-dose lercanidipine had beneficial effects on coronary dysfunctions: at month 4 of the treatment period, reactive hyperemia to short duration ischemia was improved, as was the endothelium-dependent vasodilator response (acetylcholine=68 %+/-16 % vs 11 %+/-5 % in untreated CM hamsters, P<0.05) and endothelium-independent vasodilator response (sodium nitroprusside=36 %+/-5 % vs 22 %+/-12 % in untreated CM hamsters, P<0.05). Capillary density averaged 10,879+/-474 capillaries per mm2 in papillary muscle from normal hamsters; this value did not change over time in normal hamsters and was not affected during the transition phase to heart failure in CM hamsters. Lercanidipine preserved myocardial capillary density in these conditions. Chronic exposure to lercanidipine had no impact on myocardial remodeling observed in CM hamsters. CONCLUSION: Lercanidipine had a beneficial impact on the coronary compartment in the transition phase to heart failure in a model of dilated cardiomyopathy.
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Bloqueadores de los Canales de Calcio/farmacología , Cardiomiopatías/patología , Dihidropiridinas/farmacología , Miocardio/patología , Remodelación Ventricular/efectos de los fármacos , Acetilcolina/farmacología , Animales , Capilares/patología , Cardiotónicos/farmacología , Cricetinae , Femenino , Insuficiencia Cardíaca/patología , Masculino , Mesocricetus , Nitroprusiato/farmacología , Vasodilatadores/farmacologíaRESUMEN
WB4101 (1)-related compounds 5-10 were synthesized, and their biological profile at alpha(1)-adrenoreceptor (AR) subtypes and 5-HT(1A) serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors. Moreover, their receptor selectivity was further determined in functional experiments in isolated rat prostate (alpha(1A)), vas deferens (alpha(1A)), aorta (alpha(1D)), and spleen (alpha(1B)). In functional assays, compound 5 was the most potent at alpha(1D)-ARs with a reversed selectivity profile (alpha(1D) > alpha(1A) > alpha(1B)) relative to both prototype 1 and phendioxan (2) (alpha(1A) > alpha(1D) > alpha(1B)), whereas compound 8, bearing a carbonyl moiety at position 1, was the most potent at alpha(1A)-ARs with a selectivity profile similar to that of prototypes. The least potent of the series was the trans isomer 6, suggesting that optimum alpha(1)-AR blocking activity in this series is associated with a cis relationship between the 2-side chain and the 4-phenyl ring rather than a trans relationship as previously observed for the 2-side chain and the 3-phenyl ring in 2 and related compounds. Binding affinity results were not in complete agreement with the selectivity profiles deriving from functional experiments. Although a firm explanation was not available, neutral and negative antagonism and receptor dimerization were considered as two possibilities to account for the difference between binding and functional affinities. Finally, compound 5 was selected for a modeling study in comparison with 1, mephendioxan (3), and open phendioxan (4) to achieve information on the physicochemical interactions that account for its high affinity toward alpha(1d/D)-ARs.
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Antagonistas Adrenérgicos alfa/síntesis química , Cromanos/síntesis química , Dioxanos/síntesis química , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Células CHO , Cromanos/química , Cromanos/farmacología , Cricetinae , Dioxanos/química , Dioxanos/farmacología , Células HeLa , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Próstata/efectos de los fármacos , Próstata/fisiología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Bazo/efectos de los fármacos , Bazo/fisiología , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
The effects of hypertension and of treatment with dihydropyridine-type Ca2+ antagonists and the vasodilator hydralazine on renal arterial tree were investigated in spontaneously hypertensive rats (SHR) with quantitative microanatomical techniques. Pharmacological treatment decreased to a similar extent systolic blood pressure values in SHR. Increased thickness of the tunica media of intrarenal arteries accompanied and luminal narrowing were observed in control SHR. Lercanidipine, manidipine, and nicardipine significantly countered wall thickening and luminal narrowing. Hydralazine countered luminal narrowing only. Dihydropyridines exerted renal vasocilatory activity primarily on resistance arteries, being lercanidipine the only compound active on small sized arteries.