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PHA-022121 is a novel small molecule bradykinin B

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P

A new class of peptidomimetic C5a receptor antagonists characterized by C-terminal amino acids with hydrophobic side chains is presented. Systematic optimization of the first hits led to JPE1375 (36), which was intensively characterized in vitro and in vivo. Compound 36 exhibits high microsomal stability and receptor specificity and is highly active in an immune complex mediated peritonitis model (reverse passive Arthus reaction) in mice.

A series of novel, highly potent αvβ3 antagonists based on a thiophene scaffold and containing an acylguanidine as an Arg-mimetic is described. A number of structural features, such as cyclic versus open guanidine and a variety of lipophilic side chains, carbamates, sulfonamides and β-amino acids were explored with respect to inhibition of αvβ3 mediated cell adhesion and selectivity versus αIIbβ3 binding. In addition, compound 19 was found to be active in the TPTX model of osteoporosis.

Background —Thrombosis and neointima formation limit the efficacy of coronary angioplasty (PTCA). Clinical trials have implicated the adhesion molecules integrin α IIb β 3 and integrin α v β 3 in these processes. The roles of these molecules in vascular smooth muscle cell adhesion, platelet aggregation, and the thrombotic and neointimal response to oversize porcine PTCA was investigated by use of a selective α IIb β 3 antagonist (lamifiban), a selective α v β 3 antagonist (VO514), and a combined α IIb β 3 /α v β 3 antagonist (G3580). Methods and Results —In vitro, both α v β 3 inhibitors caused dose-dependent inhibition of porcine vascular smooth muscle cell adhesion to vitronectin but not to collagen type IV, fibronectin, or laminin, whereas selective α IIb β 3 inhibition had no effect. Intravenous infusions of either α IIb β 3 inhibitor in swine profoundly inhibited ex vivo platelet aggregation to ADP, whereas selective α v β 3 inhibition had no effect. In a porcine PTCA model, intravenous infusions of the integrin antagonists were administered for 14 days after oversized balloon angioplasty injury. After PTCA, there was regional upregulation of integrin α v β 3 in the developing neointima, as assessed by immunohistochemistry. Six hours after PTCA, obstruction of lumen by thrombus was reduced significantly by α IIb β 3 inhibition compared with either control or α v β 3 inhibition (mean control, 18.7%; VO514, 18.5%; lamifiban, 6.4%; G3580, 7.9%). Twenty-eight days after PTCA, there was a significant reduction of neointima with inhibitors of either integrin (mean intima/media ratio: control, 3.08; VO514, 1.33; lamifiban, 0.97; G3580, 1.32). Conclusions —We conclude that both integrin α IIb β 3 and integrin α v β 3 participate in neointima development after experimental angioplasty.

The synthesis of a series of RGD mimetic α V β 3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective α V β 3 antagonists (vs α IIb β 3 ) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain.

Attachment of Fmoc-asparagine or glutamine to p-alkoxybenzyl alcohol type resins has always been difficult and not very effective. A very simple and effective method for the preparation of peptides terminating in asparagine or glutamine is described. The method involves quantitative attachment of Fmoc-Asp-OtBu or Fmoc-Glu-OtBu via their side-chain carboxyl group to a resin functionalized with our TMBPA linker for peptide amides. Peptide synthesis is performed using our standard Fmoc chemistry, and treatment with acid, e.g. TFA/DCM/scavenger mixtures, releases the Asn or Gln peptides.

Human immunodeficiency virus 1 (HIV-1) protease is a prime target in the search for drugs to combat the AIDS virus. The enzyme functions as a C2-symmetric dimer, cleaving the gag and gag-pol viral polyproteins at distinct sites. The possession of a twofold axis passing through the active site, has led to the design of C2-symmetrical inhibitors in the form of substrate-based transition-state analogs. One of the most active compounds of this class of inhibitors is HOE/BAY 793, which contains a vicinal diol central unit [Budt, K.-H., Hansen, J., Knolle, J., Meichsner, C., Paessens, A., Ruppert, D. & Stowasser, B. & Winkler, I. (1990) European Patent application EP0428,849; Budt, K.-H., Hansen, J., Knolle, J., Meichsner, C., Ruppert, D., Paessens, A. & Stowasser B. (1993) IXth International Conference on AIDS; Budt, K.-H., Peyman, A., Hansen, J., Knolle, J., Meichsner, C., Paessens, A., Ruppert, D. & Stowasser, B. (1995) Bioorg. Med. Chem. 3, 559-571.] The structure of this inhibitor bound to HIV-1 protease, in two different crystal forms, has been solved at 0.24-nm resolution using X-ray crystallography. In both forms, the details of the inhibitor-protease interactions revealed an overall asymmetric binding mode, especially between the central diol unit and the active-site aspartates. The main binding interactions comprise several specific H-bonds and hydrophobic contacts, which rationalize many of the characteristics of the structure/activity relationship in the class of vicinal diol inhibitors. In a general analysis of the mobility of the flap regions, which cover the active site and participate directly in binding, using our structures and the HIV protease models present in the Brookhaven databank, we found that in most structures the flexibility of the flaps is limited by local crystal contacts. However, in one of the structures presented here, no significant crystal contacts to the flap regions were present, and as a result the flexibility of the inhibitor bound flaps increased significantly. This suggests that the mobility and conformational flexibility of the flap residues are important in the functioning of HIV-1 protease, and must be considered in the future design of drugs against HIV protease and in structure-based drug design in general.

The synthesis of polyamide nucleic acids (PNAs) and derivatives thereof by different synthetic routes is described. The first strategy makes use of 9-Fluorenylmethoxycarbonyl (Fmoc)/monomethoxytrityl (Mmt) protected building blocks, whereas the second approach involves the use of Mmt/acyl protected monomers, which allows the preparation of PNADNA chimera. Additionally, a block coupling strategy is presented for the synthesis of novel phosphonic ester nucleic acids (PHONAs).

The preparation of 9-Fluorenylmethoxycarbonyl(Fmoc) protected building blocks for the synthesis of polyamide nucleic acids (PNAs) is described. Use of 4-Methoxyphenyldiphenylmethyl (Mmt)-protecting groups for the exocyclic amino function of the nucleobases enhances the solubility of the monomers and allows final deprotection by mild acid treatment. The novel synthetic route is exemplified by the synthesis of heptameric and octameric PNAs.

The preparation of novel monomethoxytrityl (Mmt) protected monomers for the synthesis of polyamide nucleic acids (PNAs) is described. The use of base-labile acyl-type nucleobase protecting groups and of a succinyl-linked solid-support offers a synthetic strategy similar to standard oligonucleotide synthesis conditions. This strategy has been successfully applied for the synthesis of PNAs of mixed base sequence.

A detailed structure-activity relationship of C 2 -symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HIV infected cell culture (IC 50 : 0.3 nM; EC 50 : 3 nM). There are well defined steric requirements for the design of the side chains P1–P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.

The 56 amino acid containing GnRH-associated peptide (GAP) may be prepared by a combination of fragment condensation and solid-phase peptide synthesis (SPPS). The solution-phase synthesis of the fragments 1–9 is described. Furthermore, we report on the selective cleavage of benzyl esters by catalytic hydrogenation in the presence of the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group. The C-terminal 15 amino acid containing fragment of GAP (10) was synthesized by SPPS.

Purpose To explore the role of integrin alpha5beta1 in proliferative vitreoretinopathy (PVR) pathogenesis by evaluating the expression alpha5beta1 on ARPE-19 cells and patient proliferative membranes, quantifying the inhibitory effects of JSM6427 (a small molecule alpha5beta1 inhibitor) on ARPE-19 cell adhesion and migration, and assessing the therapeutic potential of JSM6427 in a rabbit retinal detachment model. Methods Expression of alpha5beta1 was evaluated on activated ARPE-19 cells by flow cytometry and on PVR membranes by immunohistochemistry. ARPE-19 cells were used in fibronectin-dependent adhesion and migration assays with various concentrations of JSM6427; IC(50) was calculated. In the rabbit model, eyes were intravitreally injected with vehicle or JSM6427 on day 0 or 1 after retinal detachment; BrdU was administered intravitreally on day 3, and retinal tissues were harvested on day 3 (4 hours later) or 7. Retinal scarring, cellular proliferation, and inflammatory responses were quantified, and retinal morphology was analyzed in retinal sections. Results Activated ARPE-19 cells and PVR membranes expressed high levels of alpha5beta1; expression was low in control eyes. JSM6427 provided a dose-dependent blockade of ARPE-19 cell adhesion to fibronectin (IC(50), 7.1 +/- 2.5 microM) and inhibition of migration (IC(50), 6.0 +/- 4.5 microM). In the rabbit model, intravitreal injection of JSM6427 provided significant inhibition of proliferation of retinal cells (Muller cells, microglia, and macrophages) on days 3 and 7 after detachment and inhibition of inflammatory response and retinal scarring on day 7 after detachment. Conclusions JSM6427 is a promising treatment for PVR, with data suggesting that inhibition of alpha5beta1-fibronectin interactions addresses multiple pathways involving retinal pigment epithelial, glial, and inflammatory cells.

The integrin alpha5beta1 has been previously implicated in tumor angiogenesis, but its role in the remodeling of both blood vessels and lymphatics during inflammation is at an early stage of understanding. We examined this issue using a selective, small-molecule inhibitor of alpha5beta1 integrin, 2-aroylamino-3-{4-[(pyridin-2-ylaminomethyl)heterocyclyl]phenyl}propionic acid (JSM8757), in a model of sustained airway inflammation in mice with Mycoplasma pulmonis infection, which is known to be accompanied by robust blood vessel remodeling and lymphangiogenesis. The inhibitor significantly decreased the proliferation of lymphatic endothelial cells in culture and the number of lymphatic sprouts and new lymphatics in airways of mice infected for 2 weeks but did not reduce remodeling of blood vessels in the same airways. In inflamed airways, alpha5 integrin immunoreactivity was present on lymphatic sprouts, but not on collecting lymphatics or blood vessels, and was not found on any lymphatics of normal airways. Macrophages, potential targets of the inhibitor, did not have alpha5 integrin immunoreactivity in inflamed airways. In addition, macrophage recruitment, assessed in infected airways by quantitative reverse transcription-polymerase chain reaction measurements of expression of the marker protein ionized calcium-binding adapter molecule 1 (Iba1), was not reduced by JSM8757. We conclude that inhibition of the alpha5beta1 integrin reduces lymphangiogenesis in inflamed airways after M. pulmonis infection because expression of the integrin is selectively increased on lymphatic sprouts and plays an essential role in lymphatic growth.

The aim of this study was to show the anti-adhesive potential of an antisense oligodeoxynucleotide (ODN) approach when designed to suppress the cellular function of the alphaV integrin subunit in breast cancer cells. The alphaV integrins play major roles in favouring breast cancer spreading. In this study, we inhibited alphaV subunit synthesis in the human breast carcinoma cell line, MDA-MB231, by a partially phosphorothioated antisense oligodeoxynucleotide (5543-ODN). The alphaV antisense 5543-ODN reduced alphaV, but not actin, mRNA transcription and protein expression by 55% and 65% respectively (1 microM, 72 h). Control sense and mismatch reagents were inactive. The antisense, but not the sense and mismatch, 5543-ODN induced dose- and time-dependent inhibition of MDA-MB231 adhesion to serum, vitronectin, fibrinogen and fibronectin substrates but was inactive on adhesion to laminin. Thus, the alphaV integrin was located in adhesion structures, which were disrupted by treatment with the alphaV antisense 5543-ODN. Antisense treated cells also showed evidence of programmed cell death with the appearance of apoptotic bodies. MDA-MB231 cells express a mutant form of the pro-apoptotic factor p53; however, no changes in the expression of p53 were observed by Western blotting. Immunofluorescence did reveal an increased nuclear translocation of p53 suggesting activation of the protein, but such a translocation did not lead to significant changes in either the expression of the cyclin dependent kinase inhibitor, p21(WAF1/CIP1) the cell survival factor Bcl-2 or the pro-apoptotic factor Bax.

The alphav integrin subunit is highly expressed in osteoclasts where it dimerizes with beta1 and beta3 subunits to form receptors for vitronectin and bone sialoproteins. Inhibition of osteoclast adhesion and function has previously been achieved by alphavbeta3 antibodies or Arg-Gly-Asp-containing peptides which have the disadvantages of blocking a single receptor type, or of being rather nonspecific, respectively. Here we show that alphav integrin expression in rabbit osteoclasts can be inhibited by partially phosphorothioated antisense oligodeoxynucleotide (ODN) spanning the adenine-uracil-guanine (AUG) translational start site of the human/rabbit alphav gene, a procedure which offers the advantage of affecting all the alphav receptors with high efficiency. The alphav antisense ODN caused a dose-dependent, substrate-specific reduction of osteoclast adhesion and bone resorption. Control ODNs, such as sense, inverted, and mismatch, were without effect, providing evidence of specificity of the antisense reagent. It is likely as a consequence of loss of substrate interaction, the antisense ODN induced osteoclast retraction and apoptosis, increase of the cyclin/cyclin-dependent kinase complex inhibitor p21WAF1/CIP1, and inhibition of the cell survival gene, bcl-2. Although the expression of the cell death-promoting gene, bax, remained unchanged, a reduction of the bcl-2/bax ratio, known to underlie the intracellular signal to apoptosis, was observed. This finding led us to hypothesize that these changes could provide a link between reduction of alphav synthesis and osteoclast programmed death. In conclusion, this study provides novel insights into the use of alphav antisense ODN as an efficacious mechanism for blocking osteoclast function and underscores for the first time the involvement of integrins in bone cell apoptosis. In vivo studies may verify potential application of this ODN as alternative therapy for bone diseases.

HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin, a new B2 antagonist, was compared to R-493 (D-Ar[Hyp3-D-Phe7, Leu8]bradykinin) with respect to inhibition of the responses of seven isolated smooth muscle preparations to bradykinin. R-493 was found to exert: (a) high antagonistic activity on the rabbit jugular vein (pA2 of 8.86), (b) moderate activity on the rabbit aorta, guinea-pig ileum, hamster urinary bladder and human urinary bladder (pA2 of 5.76, 6.77, 7.16 and 7.15, respectively) and (c) a stimulatory effect on the guinea-pig trachea. On the other hand, HOE 140 showed identical apparent affinities (8.36–9.12) on all preparations except the rabbit aorta where it was inactive and the guinea-pig trachea where the compound was an antagonist (pA2: 7.42) without agonistic effect. HOE 140 is specific and selective for B2 receptors since it was inactive against angiotensin II, substance P, neurokinin A, desArg9-bradykini, noradrenaline or acetylcholine in the various preparations. R-493 inhibited the contractile effects of bradykinin competitively, while HOE 140 was not competitive event at low concentrations (7.7 × 10−9 M). These results demonstrate that HOE 140 is a potent B2 antagonist with high affinity, specific for kinin receptors and selective for the B2 receptor type, but is non-competitive. HOE 140 is the first bradykinin receptor antagonist that acts as such on the guinea-pig trachea without showing any agonistic activity.

Objective To evaluate the pharmacologic activity and tolerability of JSM6427, a potent and first selective small-molecule inhibitor of integrin α5β1, in monkey and rabbit models of choroidal neovascularization (CNV). Methods JSM6427 selectivity for α5β1 was evaluated by in vitro binding assays while the ability of JSM6427 to inhibit CNV was investigated in a laser-induced monkey model and a growth factor–induced rabbit model. Intravitreal injections of JSM6427 (100, 300, or 1000 μg) or vehicle were administered immediately after the CNV induction procedure and at weekly intervals for 4 weeks. Fluorescein angiography was performed weekly. Ocular tolerability was evaluated ophthalmoscopically and histologically in both models; additional assessments in monkeys included electroretinography, biomicroscopy, pathological examination, and analysis of JSM6427 pharmacokinetics. Results JSM6427 was highly selective for the α5β1-fibronectin interaction. Weekly intravitreal injections of JSM6427 resulted in a statistically significant dose-dependent inhibition of CNV in laser-induced and growth factor–induced models without any ocular JSM6427-related adverse effects. JSM6427 was cleared through the systemic circulation with no evidence of systemic accumulation. Conclusions Intravitreal JSM6427 provided dose-dependent inhibition of CNV in monkey and rabbit experimental models. Clinical Relevance JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration in humans.

Icatibant, a potent bradykinin (BK) antagonist specific for B2 receptors, was administered i.v. to 18 healthy males to assess its safety, pharmacokinetic, and pharmacodynamic profile for onset and duration of action. Part I (3 panels of 4 subjects) compared single 1h and 4h infusions (0.005 to 3.2 mg/kg) in ascending, double-blind, placebo-controlled design. Part II tested a 24h (0.15 mg/kg/day) vs. repeated 1h infusions (0.5 mg/kg q8h) in double-blind cross-over design. Icatibant (with 2 major metabolites) concentration was assessed by LC-MS-MS, and response by repeated i.v. bolus challenges of a BK dose selected for eliciting a 10–15 mmHg blood pressure drop with reflex tachycardia (Finapress photoplethys-mography) and facial flush (laser-Doppler blood flowmetry). BK blockade was obtained at all doses, with dose-dependent intensity and duration (Fig 1), correlating with plasma concentration and lacking hysteresis. BK dose increase (4-fold) overcame blockade, suggesting competitive inhibition. Icatib-ant has a rapid distribution and elimination (half-life 1.8h) and linear kinetics over the dose range tested. It was well tolerated up to 1.6 mg/kg but 3.2 mg/kg induced transient head/trunk flushing, itching, with one orthostatic hypo-tension. In conclusion, the ability of Icatibant to safely and sustainedly block BK effects over a wide dose range suggests an appealing therapeutic potential in conditions involving BK overproduction. Clinical Pharmacology & Therapeutics (2004) 75, P56–P56; doi: 10.1016/j.clpt.2003.11.212 Figure 1. Download figure to PowerPoint

DesArg 9 -D-Arg[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]BK is a potent and stable B 1 bradykinin (BK) receptor antagonist which was one order of magnitude more potent (IC 50 1.2 × 10 −8 M) in the isolated rabbit aorta than the known selective B 1 BK receptor antagonist, desArg 9 -[Leu 8 ]BK (IC 50 1.1 × 10 −7 M). DesArg 9 -D-Arg[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]BK is the desArg 10 derivative of Hoe 140, a new, potent, stable, selective and long-acting B 2 BK receptor antagonist. In B 2 organ preparation it was three orders of magnitude less potent than Hoe140. Since it is potent and stable it could contribute to the investigation of B 1 BK receptor function.

Aus Butyrolacton gewinnt man mit HBr und Triphenylphosphin 3-Carboxypropyl(triphenyl)-phosphonium-bromid (3), das mit Valeraldehyd in einer stereoselektiven Wittig-Reaktion (Z)-4-Nonensaure (4) liefert. 4 wird in einer gemischten Kolbe-Elektrolyse mit Glutarsaure-monomethylester (5a) zum (Z)-7-Dodecensaure-methylester (7a) gekuppelt. 7a ergibt durch LiAlH4-Reduktion und Acetylierung (Z)-7-Dodecenylacetat (10) (Looplure), das Pheromon von Trichoplusia ni (Cabbage looper). Die 7a-Ausbeute in der gemischten Kolbe-Elektrolyse wird durch die Stromdichte, den Neutralisationsgrad und besonders durch das 4/5a-Verhaltnis beeinflust.

Die Titelverbindung (Xb) wird durch Kondensation des aus dem Phosphoniumsalz (V) erhaltlichen Ylids (IX) mit dem (unbestandigen) Aldehyd (VIII) und alkalische Hydrolyse des entstandenen Esters (X) (keine Ausb.-Angabe) synthetisiert.

The preparation and use of new anchor groups for the synthesis of peptide amides by solid-phase peptide synthesis employing the Fmoc-method is described. Based on the structure of the 4,4'-dimethoxybenzhydryl group (Mbh) handles were developed, which could be cleaved by mild acid treatment to give carboxamides. The syntheses and application of Fmoc-amino-acid-(4-carboxylatomethyloxyphenyl-4'-methoxyphenyl) methyl amide and Fmoc-(4-carboxylatopropyloxyphenyl-4'-methoxyphenyl) methyl amide are described in detail. These handles were coupled to resins and a stepwise elongation of peptide chains proceeded smoothly with N alpha-9-fluorenylmethoxycarbonyl (Fmoc) amino acid derivatives using a carbodiimide/HOBt mediated reaction. The final cleavage of side-chain protecting groups and the release of the C-terminal amide moiety was achieved by the treatment with trifluoroacetic acid, dichloromethane in the presence of scavengers. Various peptides, such as the Leu-enkephalin amide and Leu-Gly-Gly-Gly-Gln-Gly-Lys-Val-Leu-Gly-NH2, which is a good substrate for F XIII, were prepared in high yields and purities.

The interaction between atrial natriuretic factor [synthetic human ANF-(103-126)] and angiotensin II (Ang II) and its influence on reperfusion arrhythmias, cardiodynamics, enzyme loss and metabolic changes were investigated in isolated ischaemic working rat hearts. Acute regional myocardial ischaemia was induced by coronary artery occlusion which was associated with ventricular fibrillation. Perfusion with 1 X 10(-9) mol/l Ang II markedly aggravated these arrhythmias. Perfusion with 1 X 10(-7) mol/l ANF, in contrast, gave protection against ventricular fibrillation and prevented Ang II-induced aggravation of ventricular fibrillation. Atrial natriuretic factor improved cardiodynamics, in particular, during reperfusion, whereas Ang II impaired cardiodynamics and increased the release of creatine kinase and lactate dehydrogenase. These adverse effects of Ang II were absent when ANF was simultaneously perfused. Compared with control hearts, myocardial tissue levels of glycogen, ATP and creatine phosphate were increased in hearts perfused with either ANF or ANF plus Ang II, whereas lactate levels decreased. Perfusion with Ang II alone led to deterioration in these metabolic parameters. These results in isolated working rat hearts suggest that ANF protects against the consequences of ischaemia and reperfusion and that functional antagonism between ANF and Ang II may contribute to this.

The preparation and application of a new linker for the synthesis of peptide amides using a modified Fmoc-method is described. The new anchor group was developed based on our experience with 4,4′-dimeth-oxybenzhydryl (Mbh)-protecting group for amides. Lability towards acid treatment was increased dramatically and results in an easy cleavage procedure for the preparation of peptide amides. The synthesis of N-9-fluorenylmethoxycarbonyl-[(5-carboxylatoethyl-2.4-dimethoxyphenyl)-4′-methoxyphenyl]-methyla-mine is reported in detail. This linker was coupled to a commercially available aminomethyl polystyrene resin. Peptide synthesis proceeded smoothly using HOOBt esters of Fmoc-amino acids. Release of the peptide amide and final cleavage of the side chain protecting groups was accomplished by treatment with trifluoroacetic acid-dichloromethane mixtures in the presence of scavengers. The synthesis of peptide amides such as LHRH and C-terminal hexapeptide of secretin are given as examples.

We have demonstrated an interaction between the effects of amiloride and atrial natriuretic factor (ANF) on the vascular system. In precontracted rabbit aortic strips the relaxant effect of a combination of ANF (10(-10) mol/l) and amiloride (10(-5) mol/l) was synergistic. The production of cyclic (c)GMP, which parallels ANF-induced relaxation of the strips, was not affected by amiloride alone up to 10(-3) mol/l, but was concentration-dependently increased in the presence of 10(-8) mol/l ANF. In spontaneously hypertensive rats (SHR) ANF-induced decreases in blood pressure were potentiated by amiloride. Binding experiments revealed an interaction between amiloride and ANF at the receptor level; binding of labelled ANF to aortic tissue was increased by amiloride but decreased by ATP. These data show that amiloride and ATP influence a mechanism that determines the sensitivity of vessels to ANF and this interaction occurs both at receptor level and at the level of transduction.

Die Titelverbindung (Xb) wird durch Kondensation des aus dem Phosphoniumsalz (V) erhaltlichen Ylids (IX) mit dem (unbestandigen) Aldehyd (VIII) und alkalische Hydrolyse des entstandenen Esters (X) (keine Ausb.-Angabe) synthetisiert.