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1.
Previous studies have shown that 1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P‐gp expression. The present study compared the equimolar efficacies of 1α‐hydroxyvitamin D3 [1α(OH)D3] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half‐life that is converted to 1,25(OH)2D3, and 1,25(OH)2D3 on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)‐directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [fxr(+/+)] and FXR knockout [fxr(‐/‐)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D3 and 1,25(OH)2D3, 1α(OH)D3 treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr(+/+) and fxr(‐/‐) mice compared to 1,25(OH)2D3 treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P‐gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D3 treatment. The higher activity of 1α(OH)D3 was explained by its rapid conversion to 1,25(OH)2D3 in tissue sites, furnishing higher plasma and tissue 1,25(OH)2D3 levels compared to following 1,25(OH)2D3‐treatment. In conclusion, 1α(OH)D3 exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH)2D3 in mice. Copyright © 2013 John Wiley & Sons, Ltd.  相似文献   

2.
Complex regional pain syndrome (CRPS) is related to microcirculation impairment associated with tissue hypoxia and peripheral cytokine overproduction in the affected limb. Previous studies suggest that the pathogenesis involves hypoxia inducible factor‐1α (HIF‐1α) and exaggerated regional inflammatory response. 1‐methylpropyl 2‐imidazolyl disulfide (PX‐12) acts as the thioredoxin‐1 (Trx‐1) inhibitor and decreases the level of HIF‐1α, and can rapidly be metabolized for Trx‐1 redox inactivation. This study hypothesized that PX‐12 can decrease the cytokine production for nociceptive sensitization in the hypoxia‐induced pain model. CD1 mice weighing around 30 g were used. The animal CRPS model was developed via the chronic post‐ischaemic pain (CPIP) model. The model was induced by using O‐rings on the ankles of the mice hind limbs to produce 3‐h ischaemia–reperfusion injury on the paw. PX‐12 (25 mg/kg, 5 mg/kg) was given through tail vein injection immediately after ischaemia. Animal behaviour was tested using the von Frey method for 7 days. Local paw skin tissue was harvest from three groups (control, 5 mg/kg, 25 mg/kg) 2 h after injection of PX‐12. The protein expression of interleukin‐1β (IL‐1β) and HIF‐1α was analysed with the Western blotting method. Mice significantly present an anti‐allodynia effect in a dose‐related manner after the PX‐12 administration. Furthermore, PX‐12 not only decreased the expression of HIF‐1α but also decreased the expression of IL‐1β over the injured palm. This study, therefore, shows the first evidence of the anti‐allodynia effect of PX‐12 in a CPIP animal model for pain behaviour. The study concluded that inhibition of HIF‐1α may produce an analgesic effect and the associated suppression of inflammatory cytokine IL‐1β in a CPIP model.  相似文献   

3.
Abstract: This review briefly surveys the conformational properties of guest ω‐amino acid residues when incorporated into host α‐peptide sequences. The results presented focus primarily on the use of β‐ and γ‐residues in αω sequences. The insertion of additional methylene groups into peptide backbones enhances the range of accessible conformations, introducing additional torsional variables. A nomenclature system, which permits ready comparisons between α‐peptides and hybrid sequences, is defined. Crystal structure determination of hybrid peptides, which adopt helical and β‐hairpin conformations permits the characterization of backbone conformational parameters for β‐ and γ‐residues inserted into regular α‐polypeptide structures. Substituted β‐ and γ‐residues are more limited in the range of accessible conformation than their unsubstituted counterparts. The achiral β,β‐disubstituted γ‐amino acid, gabapentin, is an example of a stereochemically constrained residue in which the torsion angles about the Cβ–Cγ (θ1) and Cα–Cβ (θ2) bonds are restricted to the gauche conformation. Hybrid sequences permit the design of novel hydrogen bonded rings in peptide structures.  相似文献   

4.
The combination of β‐adrenoceptor blockade and vasodilator action have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol‐A that combine these effects within a single molecule are described in this report. Intravenous labedipinedilol‐A (0.1–1.0 mg/kg) produced dose‐dependent hypotensive and bradycardia responses for above 1.0 h, significantly different from nifedipine (0.5 mg/kg, i.v.)‐induced hypotensive and reflex tachycardia activities in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐A also inhibited phenylephrine (20 μg/kg, i.v.)‐induced hypertensive and (‐)isoprenaline (0.5 μg/kg, i.v.)‐induced tachycardia effects. Oral administration of labedipinedilol‐A (5–50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the blood pressure and heart rate for 24 h but did not increase heart rate. Labedipinedilol‐A (10–7–10–5 M) competitively antagonized (‐)isoprenaline (10–10–10–4M)‐induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guinea pig tissues. Labedipinedilol‐A also prevented the rate‐increasing effects of increased extracellular Ca2+ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐A competitively antagonized CaCl2 and norepinephrine‐induced contractions with pKCa–1 and pA2 values of 8.46 ± 0.05 and 8.28 ± 0.03 and had a potent effect of inhibiting high K+‐induced vasocontraction. Furthermore, labedipinedilol‐A, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell line), KCl, norepinephrine, and Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐A (10–9–10–6 M). The binding characteristics of labedipinedilol‐A were evaluated in [3H]CGP‐12177 binding to ventricle and lung and [3H]nitrendipine and [3H]prazosin binding to brain membranes in rats. The ‐logIC50 values of labedipinedilol‐A for β1‐, β2‐, and α1‐adrenoceptor and calcium channel, were 8.17 × 10–7 M, 8.20 × 10–7 M, 2.20 × 10–8 M, and 2.46 × 10–8 M, respectively. Labedipinedilol‐A‐induced sustained depressor effect was mainly attributed to its calcium entry and α‐adrenoceptor blocking activities in the blood vessel. Sustained bradycardia effect resulted from β‐adrenoceptor and calcium entry blocking, which deleted the sympathetic activation‐associated reflex tachycardia in the heart. Drug Dev. Res. 49:94–108, 2000. © 2000 Wiley‐Liss, Inc.  相似文献   

5.
Furosemide is a loop diuretic frequently used to treat fluid overload conditions such as hepatic cirrhosis and congestive heart failure (CHF). A population‐based meta‐analysis approach in NONMEM® was used to develop a PK model characterizing the time‐course of furosemide in plasma and excretion into the urine for healthy subjects and fluid overload patients. Furosemide PK data from healthy subjects receiving 80 mg of oral furosemide were supplemented with additional individual and aggregate plasma concentration and urinary excretion versus time data from the literature after intravenous (i.v.) or oral furosemide administration (10–500 mg) to healthy subjects or fluid overload patients. A three‐compartment model with zero‐order input following i.v. administration (or first‐order absorption using a Weibull function after oral administration) and first‐order elimination best described furosemide PK. A covariate analysis identified creatinine clearance (CLCR) as a statistically significant predictor of renal clearance (CLR), with a population mean CLR of 4.67, 3.11, 1.95 and 1.17 l/h for a subject with normal renal function (CLCR = 120 ml/min) or mild (CLCR = 80 ml/min), moderate (CLCR = 50 ml/min) or severe (CLCR = 30 ml/min) renal impairment. Oral bioavailability was 59.1% and non‐renal clearance was 2.02 l/h. A PC‐VPC and other model diagnostics demonstrated that the population PK model can reasonably predict the rate of urinary furosemide excretion over time using dosing history and commonly available demographic data, allowing for convenient assessment of PK‐PD relationships for furosemide when given alone or in combination with other agents used to treat fluid overload conditions. Copyright © 2013 John Wiley & Sons, Ltd.  相似文献   

6.
Abstract: The novel Cα‐tetrasubstituted α‐amino acid Cα‐methyl, Cα‐cyclohexylglycine was prepared by hydrogenation of its Cα‐methyl, Cα‐phenylglycine precursor. Terminally protected homodi‐, homotri‐, and homotetrapeptides from Cα‐methyl, Cα‐cyclohexylglycine and co‐oligopeptides to the pentamer level in combination with Gly or α‐aminoisobutyric acid residues were prepared by solution methods and fully characterized. The results of a conformational analysis, performed by use of Fourier transform infrared (FT‐IR) spectrophotomet absorption, 1H NMR, and X‐ray diffraction techniques, support the contention that this Cα‐methylated, Cβ‐trisubstituted aliphatic α‐amino acid is an effective β‐turn and 310‐helix inducer in tri‐ and longer peptides as its Cα‐methyl valine parent compound, but partially divergent from the corresponding aromatic Cα‐methyl, Cα‐diphenylmethylglycine residue, known to promote folded and fully extended structures to a significant extent in these oligomers.  相似文献   

7.
Vitamin D3 and the synthetic vitamin D analogs, 1α‐hydroxyvitamin D3 [1α(OH)D3], 1α‐hydroxyvitamin D2 [1α(OH)D2] and 25‐hydroxyvitamin D3 [25(OH)D3] were appraised for their vitamin D receptor (VDR) associated‐potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D3 and 1α(OH)D2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3] and 1α,25‐dihydroxyvitamin D2 [1,25(OH)2D2], respectively. 1α(OH)D2 may also be activated by CYP24A1 to 1α,24‐dihydroxyvitamin D2 [1,24(OH)2D2], another active VDR ligand. 25(OH)D3, the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D3, is activated by CYP27B1 in the kidney to 1,25(OH)2D3. In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α‐hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D3 > 1248 nmol/kg 25(OH)D3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D3. Except for 1.21 nmol/kg 1α(OH)D2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH)2D3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D3 and 25(OH)D3 exhibit cholesterol lowering properties upon activation to 1,25(OH)2D3: 1α(OH)D3 is rapidly activated by liver enzymes and 25(OH)D3 is slowly activated by renal Cyp27b1 in mouse.  相似文献   

8.
Arginine–glycine–aspartic acid (RGD)‐containing peptides have been traditionally used as PET probes to noninvasively image angiogenesis, but recently, small selective molecules for α5β1 integrin receptor have been developed with promising results. Sixty‐one antagonists were screened, and tert‐butyl (S)‐3‐(2‐((3R,5S)‐1‐(3‐(1‐(2‐fluoroethyl)‐1H‐1,2,3‐triazol‐4‐yl)propanoyl)‐5‐((pyridin‐2‐ylamino)methyl)pyrrolidin‐3‐yloxy)acetamido)‐2‐(2,4,6‐trimethylbenzamido)propanoate (FPMt) was selected for the development of a PET tracer to image the expression of α5β1 integrin receptors. An alkynyl precursor (PMt) was initially synthesized in six steps, and its radiolabeling was performed according to the azide–alkyne copper(II)‐catalyzed Huisgen's cycloaddition by using 1‐azido‐2‐[18F]fluoroethane ([18F]12). Different reaction conditions between PMt and [18F]12 were investigated, but all of them afforded [18F]FPMt in 15 min with similar radiochemical yields (80–83%, decay corrected). Overall, the final radiopharmaceutical ([18F]FPMt) was obtained after a synthesis time of 60–70 min in 42–44% decay‐corrected radiochemical yield. Copyright © 2014 John Wiley & Sons, Ltd.  相似文献   

9.
Abstract: A protected tridehydropeptide containing (Z)‐β‐(3‐pyridyl)‐α,β‐dehydroalanine (ΔZ3Pal) residue, Boc‐Leu‐ΔZ3Pal‐Leu‐OMe ( 1 ), was synthesized via Erlenmeyer azlactone method. X‐ray crystallographic analysis revealed that the peptide 1 adopts an extended conformation, which is similar to that of a ΔZPhe analog, Boc‐Leu‐ΔZPhe‐Leu‐OMe ( 2 ).  相似文献   

10.
11.
Abstract: Using different stereoselective chemical and chemoenzymatic approaches we synthesized the chiral, Cα‐methylated α‐amino acid l ‐(αMe)Nva with a short, linear side‐chain. A set of terminally protected model peptides to the pentamer level containing either (αMe)Nva or Nva in combination with Ala and/or Aib was prepared using solution methods and characterized fully. Two (αMe)Nva peptides were also synthesized using side‐chain hydrogenation of the corresponding Cα‐methyl, Cα‐allylglycine (Mag) peptides. A detailed solution and crystal‐state conformational analysis based on FT‐IR absorption, 1H NMR and X‐ray diffraction techniques allowed us to define that: (i) (αMe)Nva is an effective β‐turn and 310‐helix former; and (ii) the relationship between (αMe)Nva chirality and the screw sense of the turn/helix formed is that typical of protein amino acids, i.e. l ‐(αMe)Nva induces the preferential formation of right‐handed folded structures. In more general terms, this study reinforced previous conclusions that peptides based on α‐amino acids with a Cα‐methyl substituent and a Cα‐linear alkyl substituent are characterized by a strong tendency to fold into turn and helical structures.  相似文献   

12.
This article describes new deltorphin I analogs in which phenylalanine residues were replaced by the corresponding (R) or (S)‐α‐benzyl‐β‐azidoalanine, α‐benzyl‐β‐(1‐pyrrolidinyl)alanine, α‐benzyl‐β‐(1‐piperidinyl)alanine, and α‐benzyl‐β‐(4‐morpholinyl)‐alanine residues. The potency and selectivity of the new analogs were evaluated by a competitive receptor binding assay in the rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). The affinity of analogs containing (R) or (S)‐α‐benzyl‐β‐azidoalanine in position 3 to δ‐receptors strongly depended on the chirality of the α,α‐disubstituted residue. The conformational behavior of peptides modified with (R) or (S)‐α‐benzyl‐β‐(1‐piperidinyl)Ala, which displays the opposite selectivity, was analyzed by 1H and 13C NMR. The μ‐selective Tyr‐d ‐Ala‐(R)‐α‐benzyl‐β‐(1‐piperidinyl)Ala‐Asp‐Val‐Val‐Gly‐NH2 lacks the helical conformation observed in the δ‐selective Tyr‐d ‐Ala‐(S)‐α‐benzyl‐β‐(1‐piperidinyl)Ala‐Asp‐Val‐Val‐Gly‐NH2. Our results support the proposal that differences between δ‐ and μ‐selective opioid peptides are attributable to the presence or absence of a spatial overlap between the N‐terminal message domain and the C‐terminal address domain.  相似文献   

13.
The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO‐4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO‐4641, a sphingosine 1‐phosphate receptor modulator. Using a two‐compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO‐4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO‐4641 was described by an indirect‐response model. The indirect‐response model had an Imax value of 0.828 and an IC50 value of 1.29 ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO‐4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies. Copyright © 2010 John Wiley & Sons, Ltd.  相似文献   

14.
Based on a previous report that α‐tetralone (3,4‐dihydro‐2H‐naphthalen‐1‐one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7‐substituted α‐tetralone derivatives. Arylalkyloxy substitution on C7 of the α‐tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase‐B isoform with all compounds possessing IC50 values in the submicromolar range (0.00089–0.047 μm ). The C7‐substituted α‐tetralones also were highly potent monoamine oxidase‐A inhibitors with thirteen (of fifteen) compounds possessing IC50 values in the submicromolar range (0.010–0.741 μm ). The α‐tetralones were, however, in each instance selective for monoamine oxidase‐B over the monoamine oxidase‐A isoform. Dialyses of enzyme–inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase‐A inhibitor, inhibition of monoamine oxidase‐B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α‐tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7‐substituted α‐tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression.  相似文献   

15.
Abstract: A simple, efficient and stereospecific approach for the homologation of urethane‐protected α‐amino acids to β‐amino acids by the Arndt–Eistert method employing Fmoc‐/Boc‐α‐amino acid and 2‐(1H‐benzotriazole‐1‐yl)‐1,1,3,3‐tetramethyl‐uronium hexafluorophosphate mixture for the acylation of diazomethane synthesizing the key intermediates Fmoc‐/Boc‐α‐aminodiazomethanes as crystalline solids is described.  相似文献   

16.
Abstract: Hofmann rearrangement of Nα‐Boc‐l ‐Gln‐OH mediated by a polymer‐supported hypervalent iodine reagent poly[(4‐diacetoxyiodo)styrene] (PSDIB) in water afforded Nα‐Boc‐l ‐α,γ‐diaminobutyric acid (Boc‐Dab‐OH, 1 ) in 87% yield. Nα‐Z‐derivative (Z‐Dab‐OH, 2 ) was prepared with PSDIB in 83% yield. Since the reaction of Nα‐Fmoc‐Gln‐OH by this procedure did not proceed because of the insolubility of Fmoc‐Gln‐OH in aqueous media, we synthesized Fmoc‐Dab(Boc)‐OH ( 5 ) from 2 in 54% yield. Polymyxin B heptapeptide (PMBH) which contains four Dab residues was successfully synthesized in a solution‐phase synthesis.  相似文献   

17.
1. It is known that the α4‐subunit is likely to occur in the brain predominantly in α4β3δ receptors at extrasynaptic sites. Recent studies have revealed that the α1‐, α4‐, γ2‐ and δ‐subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABAA receptors containing human (H) and rat (R) α14‐, β23‐ and γ2S/δ‐subunits in Xenopus oocytes using the two‐electrode voltage‐clamp technique. 2. Both Hα1β3δ and Hα4β3γ2S receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the α4β3δ combination was more sensitive to agonist action than the α4β3γ2S receptor, we observed extremely small GABA‐ and pentobarbital‐activated currents at the wild‐type Hα4β3δ receptor. However, GABA and pentobarbital activated the wild‐type Rα4β3δ receptor with high potency (EC50 = 0.5 ± 0.7 and 294 ± 5 μmol/L, respectively). 3. Substituting the Hα4 subunit with Rα4 conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC50 and increased Imax. When the Hα4 subunit was combined with the Rβ3 and Rδ subunit in a heteropentameric form, the amplitude of GABA‐ and pentobarbital‐activated currents increased significantly compared with the wild‐type Hα4β3δ receptor. 4. Thus, the results indicate that the Rα4β3δ, Hα1β3δ and Hα4β3γ2S combinations may contribute to functions of extrasynaptic GABAA receptors. The presence of the Rα4 subunit at recombinant GABAA receptors containing the δ‐subunit is a strong determinant of agonist action. The recombinant Hα4β3δ receptor is a less sensitive subunit composition in terms of agonist activation.  相似文献   

18.
Isoeugenodilol, derived from isoeugenol, was investigated under in vivo and in vitro conditions. Isoeugenodilol (0.1, 0.5, 1.0, and 3.0 mg kg–1, i.v.) produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. Isoeugenodilol (0.5 mg kg–1, i.v.) also markedly inhibited both the tachycardia effects induced by (‐) isoproterenol and arterial pressor responses induced by phenylephrine. A single oral administration of isoeugenodilol at doses of 10, 30, and 100 mg kg–1 dose‐dependently reduced blood pressure, with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, isoeugenodilol competitively antagonized the (‐) isoproterenol‐induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curve of (‐) isoproterenol suggested that isoeugenodilol was a β12‐adrenoceptor competitive antagonist. The apparent pA2 values were 7.33 ± 0.12 in the right atria, 7.80 ± 0.09 in the left atria, and 7.26 ± 0.11 in the trachea, indicating that isoeugenodilol was a nonselective β‐adrenoceptor blocker. In thoracic aorta experiments, isoeugenodilol also produced a competitive antagonism of norepinephrine‐induced contraction with a pA2 value of 7.47 ± 0.45. In isolated atria of reserpinized rats, cumulative additions of isoeugenodilol and propranolol produced significantly cardiodepressant responses at high concentrations (10–5 M) and were without intrinsic sympathomimetic activity (ISA). In isolated rat thoracic aorta, isoeugenodilol more potently relaxed the contractions induced by norepinephrine (3 × 10–6 M) than those by high K+ (75 mM). The vasorelaxant effects of isoeugenodilol on norepinephrine‐induced contractions were attenuated by pretreatment with tetraethylammonium (TEA) and glibenclamide, implying the involvement of K+ channel opening. In addition, isoeugenodilol inhibited norepinephrine‐induced biphasic contraction; it affected the fast phase significantly more than the slow phase. Furthermore, the binding characteristics of isoeugenodilol and various β‐adrenoceptor antagonists were evaluated in [3H]CGP‐12177 binding to rat ventricle and lung tissues and [3H]prazosin binding to brain membranes. The ranking order of inhibition for [3H]CGP‐12177 binding on β‐adrenoceptor was propranolol > labetalol > isoeugenodilol, and that for [3H]prazosin binding to α‐adrenoceptors was isoeugenodilol > labetalol. Furthermore, isoeugenodilol inhibited lipid peroxidation induced by Fe2+ and ascorbic acid with IC50 of 0.74 ± 0.03 mM, indicating that it possesses the antioxidant activity inherent in isoeugenol. In conclusion, isoeugenodilol was found to be a new generation α/β‐adrenoceptor antagonist with vasorelaxant activity by inhibiting Ca2+ channel, receptor‐mediated Ca2+ mobilization and by K+ channel opening, and to have additional potentially antioxidant effects. Drug Dev. Res. 51:29–42, 2000. © 2000 Wiley‐Liss, Inc.  相似文献   

19.
Abstract: Using a chemo‐enzymatic approach we prepared the highly lipophilic, chiral, Cα‐methylated α‐amino acid (αMe)Aun. Two series of terminally protected model peptides containing either d ‐(αMe)Aun in combination with Aib or l ‐(αMe)Aun in combination with Gly were synthesized using solution methods and fully characterized. A detailed solution conformational analysis, based on FT‐IR absorption, 1H NMR and CD techniques, allowed us to determine the preferred conformation of this amino acid and the relationship between chirality at its α‐carbon atom and screw sense of the helix that is formed. The results obtained strongly support the view that d ‐(αMe)Aun favors the formation of the left‐handed 310‐helical conformation.  相似文献   

20.
Abstract: A series of short, amphipathic peptides incorporating 80% Cα,Cα‐disubstituted glycines has been prepared to investigate amphipathicity as a helix‐stabilizing effect. The peptides were designed to adopt 310‐ or α‐helices based on amphipathic design of the primary sequence. Characterization by circular dichroism spectroscopy in various media (1 : 1 acetonitrile/water; 9 : 1 acetonitrile/water; 9 : 1 acetonitrile/TFE; 25 mm SDS micelles in water) indicates that the peptides selectively adopt their designed conformation in micellar environments. We speculate that steric effects from ith and ith + 3 residues interactions may destabilize the 310‐helix in peptides containing amino acids with large side‐chains, as with 1‐aminocyclohexane‐1‐carboxylic acid (Ac6c). This problem may be overcome by alternating large and small amino acids in the ith and ith + 3 residues, which are staggered in the 310‐helix.  相似文献   

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