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I Rozas

Publications and source records attributed to I Rozas.

13 recordsLinked to original sources
PubMed2000

New aromatic iminoimidazolidine derivatives as alpha1-adrenoceptor antagonists: a novel synthetic approach and pharmacological activity.

The design, synthesis and alpha1-adrenoceptor antagonism of a series of bis-imidazoline (1a, 2a, 3a and 4a) and bis-guanidine (1b, 2b, 3b and 4b) diphenyl derivatives are reported. All of these compounds fulfill the conditions of the most recent pharmacophore proposed for alpha1-adrenoceptors and found in the literature. Besides, a novel synthetic approach to the preparation of 2-(arylimino)imidazolidine derivatives is described. All the tested compounds, except the bis-guanidinium derivative 3b, inhibit the contractile responses induced by noradrenaline in aortic rings of rat and rabbit in a dose-dependent manner. Our results indicate that, even though some discrepancies are observed in terms of the alpha1 subtype targeted by this new family of compounds, they show an interesting profile as antagonists of alpha1-adrenoceptors and a new prototype, compound 1a, has been found deserving further development.

Adrenergic alpha-Antagonists↗
PubMed1998

Similarity studies on guanidinium, imidazolinium, and imidazolium cations: toward new bradykinin antagonists.

Bradykinin (BK) is a potent nociceptive agent and its antagonists show analgesic activity. In the search for new antagonists of BK, the design of nonpeptidic derivatives with different terminal cations has been considered. Among these new antagonists, the guanidinium cations, which appear not only in the terminal arginine residues of BK but also in several nonpeptidic antagonists, will be substituted by groups with characteristics similar in terms of electrostatic potential, electron density, shape, etc. Several similarity indexes have been calculated for guanidinium, 2-aminoimidazolinium, and 2-aminoimidazolium cations and their corresponding neutral species to design new nonpeptidic BK antagonists. The geometric and electronic characteristics of the molecules were compared by means of: (1) the Carbo index, (2) the Hodgkin index, and (3) a shape similarity index based on the volume of each molecule as defined by a certain electron density. Molecular geometries and energies were optimized by ab initio calculations at the B3LYP/6311+2G** level. The molecular electrostatic potential (MEP) and the electron density (rho) were then computed in a cubic grid of points around each molecule. These molecular properties were used to calculate similarity indexes with the guanidinium cation or guanidine as the reference molecule in each family. In addition, three-dimensional similarity maps were generated to localize those molecular areas more alike in each of the sets.

Bradykinin↗
PubMed1997

Molecular modeling of (E)-1-alkyl-4(3)-[2-(1H-azolyl)vinyl]-pyridinium salts and evaluation of their behavior towards choline acetyltransferase.

A new type of extended pi-system aza-analogue of (E)-4-[2-(1-naphthylvinyl)]-1-substituted pyridinium salts (NVP+) has been designed and its inhibitory activity towards choline acetyltransferase (ChAT) has been evaluated in vitro. Among the several examples of the title quaternary salts synthesized 2 and 3, the indolylvinylpyridinium salt 2e is the only one to show a very low ChAT inhibition. The molecular modeling study is highly illustrative of their behavior towards ChAT and interaction with the recognition site. Thus, several selected cations together with the reference NVP+ compound 1a were studied at the PM3 and AM1 levels respectively. At the global minima, all the compounds are planar, which, from the electron charge distribution, shows a degree of polarization similar to the NVP+ model compound 1a. However, the fitting of all optimized structures indicated that only the indole derivative 2e showed the same aromatic fragment orientation as 1a, which allows us to define a volume that is not accessible to ligands in the enzyme and consequently to a refined model of the choline acetyltransferase recognition site.

Animals↗
PubMed1995

Interrelation between electrostatic and lipophilicity potentials on molecular surfaces.

Molecular electrostatics and lipophilicity are two important properties included in quantitative structure-activity relationships (QSARs) employed for rational drug design. The molecular electrostatic potential (MEP) provides information on the position, distribution, and extent of electrophilic and nucleophilic regions around a molecule. Similarly, the solvent affinity can be represented by a local phenomenological potential of semiempirical nature: the molecular lipophilicity potential (MLP). Although a simultaneous, three-dimensional display of MEP and MLP is possible, it may not provide a practical tool for comparing molecules. In this work, we deal with the simpler two-dimensional maps of the entire molecular surface projected onto an MEP-MLP plane. We analyze how these maps change with the following factors: (1) composition and molecular geometry, (2) the quality of the computation of MEP, and (3) the parameter set used for evaluating the lipophilicity potential. The approach is used to compare series of pyrazole derivatives. The methodology is useful in assessing molecular similarity, as well as in establishing the nature of differences between compounds.

Chemical Phenomena↗
PubMed1994

Synthesis of 4-alkylpyrazoles as inhibitors of liver alcohol dehydrogenase.

Theoretical studies by shape analysis of the molecular electrostatic potential on the van der Waals surfaces of a set of 4-alkylpyrazoles predicted 4-isopentyl derivative as a good inhibitor of liver alcohol dehydrogenase. Thus, the new 4-isopentyl and the already known 4-octylpyrazole have been prepared by a novel route. The isopentyl derivative has been tested as inhibitor of horse liver alcohol dehydrogenase giving the result predicted by the theoretical studies.

Alcohol Dehydrogenase↗
PubMed1994

Effect of branching in 4-alkylpyrazoles on liver alcohol dehydrogenase inhibition: a shape analysis study.

Shape analysis methodology is applied to the study of 4-alkylpyrazoles which are known inhibitors of liver alcohol dehydrogenase. Elongation of the alkyl chain increases the inhibitory power, whereas branching of the chain diminishes the activity. These two counterpoised effects are studied simultaneously in a selected set of 4-alkylpyrazoles. A systematic conformational analysis followed by topological characterization of the van der Waals surfaces of all the local minima restricts the conformational space to potential bioactive structures. The analysis of the interrelation between the molecular electrostatic potential and van der Waals surfaces provides certain shape codes characteristic of each 4-alkylpyrazole. In both topological analyses (van der Waals surfaces and molecular electrostatic potential-van der Waals surface interrelations) graphical representations and analytical methods were used. A good correlation between the shape codes and the inhibitory activity is found for the linear derivatives. For branched pyrazoles, a tendency in their inhibitory power is predicted. Isopentylpyrazole is suggested to have the same inhibitory profile as 4-butylpyrazole, the linear derivative with one less carbon atom.

Alcohol Dehydrogenase↗
PubMed1991

Short-term effects of administration of anticonvulsant drugs on free carnitine and acylcarnitine in mouse serum and tissues.

1. The short-term evolution of concentrations of free carnitine and acylcarnitine was studied in the serum, liver, kidney, heart and skeletal muscle of mice after administration of single therapeutic doses of the anticonvulsant drugs, valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT) and phenobarbitone (PHB). 2. The effects of the drugs were immediate but transitory, control levels of free carnitine and acylcarnitine having been recovered or almost recovered in serum and in all tissues 8 h post administration (p.a.). 3. VPA was the only drug that significantly reduced free carnitine concentration in serum, which recovered control levels by 4 h p.a. 4. All the drugs studied brought about marked deficits of serum acylcarnitine, which had disappeared 2 h p.a. in the case of VPA and not until 8 h p.a. for CBZ, PHT or PHB. 5. The minimum concentrations of free carnitine and acylcarnitine in serum were invariably associated with the maximum concentration of drug in serum. 6. Free carnitine concentration was not affected by VPA in any tissue, PHT and PHB brought about significant deficits in heart and kidney, and CBZ a significant deficit in muscle. 7. Acylcarnitine concentration was significantly reduced in heart, kidney and muscle by CBZ, PHT and PHB, but in liver the effects of all drugs were very small. 8. These results are compatible with the hypothesis that the primary cause of anticonvulsant-induced alteration of carnitine metabolism is interference with renal reabsorption of carnitine.

Animals↗
PubMed1991

Alteration of renal carnitine metabolism by anticonvulsant treatment.

We administered therapeutic doses of valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PHB) to mice for 7 days, and 8 hours after the final dose we measured the concentrations of carnitine in serum, liver, kidney, skeletal muscle, and heart, and in the 7 days' accumulated urine. The results for serum and urine show that VPA induced a significant increase in renal clearance of acylcarnitine without affecting that of free carnitine, whereas CBZ, PHT, and PHB significant increased clearance of free carnitine but not that of acylcarnitine. Thus, VPA appears to reduce tubular resorption of acylcarnitine, and CBZ, PHT, and PHB appear to reduce tubular resorption of free carnitine.

Ammonia↗
PubMed1990

A structure-reactivity study of the binding of acetylglutamate to carbamoyl phosphate synthetase I.

The requirements for binding at the N-acetyl-L-glutamate binding site of carbamoyl phosphate synthetase I were studied by the displacement of the activator from the central enzyme complex by analogs. Two carboxyls are essential and the acetamido group, if linked to the alpha-carbon, enhances binding 5000-fold. The subsite for the delta-carboxyl is mobile with respect to that for the alpha-carboxyl. Mixtures of complementary fragment of acetylglutamate do not bind, indicating a strong 'chelate' effect. Substituents revealed the existence of steric constraints around the delta-carboxyl, the alpha and gamma-carbons, and the whole of the acetamido group. However, phenyl substituents at the beta-carbon did not hamper binding, indicating that substituents at the beta-carbon face the solution. This is consistent with binding of acetylglutamate as the minimum-energy conformer. All analogs binding with high affinity are activators. Some analogs that bind poorly are competitive inhibitors. They appear to bind preferentially to a low-affinity conformation adopted by the site when the products dissociate and the substrates bind. The acetamido group plays no role in the binding of the inhibitors but it is crucial for the binding of the activators, and the high- and low-affinity conformations of the site differ markedly in structural selectivity.

Acetamides↗
PubMed1990

Effects of acute valproate administration on carnitine metabolism in mouse serum and tissues.

Carnitine concentrations in serum, liver, kidney, muscle and heart were determined 30 min, 2 hr and 4 hr after administration of single 50 mg/kg doses of valproic acid (VPA) or octanoic acid (OTA) of fasting mice. Half an hour post-administration (p.a.) of VPA, free carnitine concentrations were smaller than in controls in serum, liver, kidney and heart. Four hr p.a., the effects of VPA had disappeared from all the carnitine sources, which now had concentrations that were not significantly different from those of controls. The effects of OTA are different from, and sometimes the opposite of, those of VPA, showing that the effects of VPA are specific to it. Hyperammonemia, on the other hand, was greatest 4 hr p.a. of VPA. These findings show that the effect of VPA on carnitine metabolism is immediate but transient, and accordingly suggest that the carnitine deficiency observed in patients under prolonged treatment with VPA-containing anticonvulsants must be due to a more complex mechanism than direct interaction between carnitine and VPA.

Ammonia↗
PubMed1990

Free carnitine and acylcarnitine levels in sera of alcoholics.

We report the free, acyl-, and total carnitine contents of 49 clinically healthy volunteers and 167 chronic alcoholics with various clinically and/or anatomopathologically identified degrees of hepatic affection. There was a gradual upward trend in carnitine levels as the degree of hepatic affection increased. In cirrhotic patients, both free and acylcarnitine levels were significantly higher than normal, but there was no systematic hypercarnitinemia in other stages of alcoholism; on the contrary, noncirrhotic alcoholic patients accounted for 82.6% of all hypocarnitinemia cases. Hypercarnitinemia among cirrhotic alcoholics was due chiefly to increased free carnitine concentrations. Acylcarnitine levels in patients with hepatic steatosis were significantly higher than those in normal subjects (P less than 0.001), but there were no other statistically significant differences in either acyl- or free carnitine levels between normals on the one hand and, on the other, patients with hepatic steatosis, alcoholic hepatitis, slight hepatopathy, or chronic hepatopathy without portal hypertension.

Acetylcarnitine↗
PubMed1989

Carnitine deficiency associated with anticonvulsant therapy.

Valproic acid therapy is known to be associated with carnitine deficiency in adult as well as young epileptic patients. In a study of the possible existence of such side-effects with other anticonvulsants, 76.5% of adult patients treated with valproate were deficient in serum free carnitine, with acylcarnitine levels significantly higher than in controls (p less than 0.01), while the carnitine deficiency rate in a group of patients treated with anticonvulsants other than valproate was 21.5%. Since in clinical practice only about one fifth of patients are treated with valproate, this means that about 15% of epileptics are carnitine deficient because of valproate treatment and 17% because of other anticonvulsants. The mechanisms and clinical and biological consequences of the carnitine deficiency associated with antiepileptic drugs other than valproate are not known.

Adolescent↗