Synthesis, biological evaluation, and pharmacophore generation of new pyridazinone derivatives with affinity toward alpha(1)- and alpha(2)-adrenoceptors.

A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both alpha(1)- and alpha(2)-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the alpha(1)-adrenoceptor, with K(i) values in the low nanomolar range. The polymethylene chain constituting the spacer between the furoylpiperazinyl pyridazinone and the arylpiperazine moiety was shown to influence the affinity and selectivity of these compounds. Particularly, a gradual increase in affinity was observed by lengthening the polymethylene chain up to a maximum of seven carbon atoms. In addition, compound 3k, characterized by a very interesting alpha(1)-AR affinity (1.9 nM), was also shown to be a highly selective alpha(1)-AR antagonist, the affinity ratio for alpha(2)- and alpha(1)-adrenoceptors being 274. To gain insight into the structural features required for alpha(1) antagonist activity, the pyridazinone derivatives were submitted to a pharmacophore generation procedure using the program Catalyst. The resulting pharmacophore model showed high correlation and predictive power. It also rationalized the relationships between structural properties and biological data of, and external to, the pyridazinone class.

Bronchodilator activity of theophylline derivatives substituted at the 7-position.

Theophylline derivatives with several groups linked at the 7-position were synthesized and their pharmacological activities were studied on guinea pig. Relaxant action in the tracheal muscle was increased in comparison with that of theophylline when the 3(2H)-pyridazinone system was linked to 7-(2-ethyl)-theophylline through the piperazine ring, but decreased when the 7-(2-ethyl)-theophylline was linked to 3(2H)-pyridazinone ring through an amino group.

Synthesis and pharmacological evaluation of 6-(7-theophylline)-3(2H)-pyridazinone.

Since the introduction of theophylline (1) as the first PDE-inhibitor used in the treatment of asthma, there has been intense activity in this area of therapy to design drugs with improved potency and efficacy. Derivatives of theophylline and other purine analogs were prepared and tested as PDE-inhibitors and cardiac stimulants, some of them being several times more active than theophylline. A variety of 4,5-dihydro-6-phenyl-3(2H)-pyridazinone derivatives are PDE-inhibitors like CI-914 (2) which produced a cardiotonic effect accompanied by only slight decreases in blood pressure and moderate increases in heart rate. In a recent report some 6-phenyl-3(2H)-pyridazinones showed a bronchospasmolytic effect more marked than that of xanthines. In this paper we report the synthesis and pharmacological profile of 6-(7-theophylline)-3(2H)-pyridazinone; the synthesis is shown in Scheme 1.

Structure-activity relationships of some 1,4-benzodioxane aryl-piperazine derivatives as alpha-blocking agents.

The synthesis of eight novel 1,4-benzodioxane derivatives is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic alpha-adrenoceptors of isolated rat vas deferens. Structure-activity relationships are discussed.

Constituents of essential oil of Commiphora guidotti.

From the essential oil of Commiphora guidotti seven sesquiterpene hydrocarbons and a furanosesquiterpenoid, furanodiene, were isolated.

Synthesis and Ca-antagonist activity of some benzhydryl derivatives.

The preparation of a series of benzhydryl derivatives is described. Their activities as Calcium-antagonists were evaluated on the taenia coli of the guinea-pig. These new compounds show lower activities as Ca-antagonists than Cinnarizine.

Synthesis and pharmacological evaluation of propranolol-cyclic analogues.

Three propranolol analogues, bearing the oxygen of the --OH group enclosed in a 1,4-dioxanic rigid system, were synthetized. The lack of beta-blocking activity found for these compounds demonstrates the important role played by a free--OH group in the drug-receptor interaction.

The effect of some flavolignans on lipid synthesis in ethanol-intoxicated hepatocytes in primary culture.

Rat liver cells in primary culture have been used to investigate the effect of ethanol and of two flavolignans 3,7-dihydroxy-2-(1,4-benzodioxan-6-yl)chroman-4-one (I) and 3,7-dihydroxy-2-[(2,3-diphenyl)-1,4-benzodioxan-6-yl]chroman-4-one (II) on the incorporation of [2-3H]-glycerol into lipids. Ethanol produces a decrease of the incorporation of labelled glycerol into lipids, whereas at the longest times of incubation flavolignans have an opposite effect. Neutral lipid/phospholipid labelling ratio is modified by ethanol in favour of neutral lipids. This action is counteracted by both flavolignans, which are therefore able to hinder, at least partially, the actions of ethyl alcohol on liver lipid metabolism.

Structure-activity relationships in a series of 8-substituted xanthines as bronchodilator and A1-adenosine receptor antagonists.

Four new derivatives of 8-piperazine ethyl xanthine were synthesized and their bronchospasmolytic activity and A1-adenosine affinity were studied. Their relaxant action in the tracheal muscle was lower than that of theophylline and that of theophylline derivatives substituted at the 7-position. Only compound 9, where the methyl group in the 1-position of the theophylline was substituted by an isobutyl group, shows a good affinity towards the A1-adenosine receptor.

Synthesis of new pyridazinone derivatives and their affinity towards alpha1-alpha2-adrenoceptors.

A series of 3(2H)-pyridazinone derivatives was evaluated for their affinity in vitro towards alpha1-alpha2-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the alpha1-adrenoceptor (with Ki values in the subnanomolar range), and a gradual increase in affinity was observed by increasing the polymethylene chain length of this series up to a maximum of six and seven carbon atoms, when the fragment 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl is linked in 5 position of the 3(2H)-pyridazinone ring, while a slight decrease was found for the higher homologues. Increasing the chain length when the 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl group is linked in 6 position of the 3(2H)-pyridazinone ring, had a different effect: there is the highest affinity when the polymethylene chain is of four carbon atoms. The alkylic chain, a spacer between the two major constituents of the molecule, can influence the affinity and the selectivity.

Synthesis and pharmacological evaluation of some WB4101 analogues bearing a naphthodioxanic nucleus.

Three WB4101 analogues, bearing a 1,4-naphthodioxanic system, were synthesized. The decrease of the alpha-blocking activity found for these compounds, showed that extension of the aromatic area in the dioxanic moiety of such benzodioxanic derivative, hinders the drug-receptor interaction.

Comparative molecular field analysis of some pyridazinone-containing alpha1-antagonists.

Diverse series of piperazines linked at N1 to 4, 5, or 6 positions of 3-(2H)-pyridazinone ring and at N4, by a suitable alkyl spacer, to some classical alpha1-adrenoceptor pharmacophore moieties, were tested in vitro for their alpha1-adrenoceptor antagonist activity. The modeling of their biological activity (pKb) by comparative molecular field analysis led to the development of a statistically significant partial least squares (PLS) model able to detect at 3-D level the main physicochemical interactions responsible for alpha1-adrenoceptor antagonist activity.

Structure-activity relationships in a series of 8-substituted xanthines as A1-adenosine receptor antagonists.

A series of 8-substituted xanthines were synthesized and their affinity in vitro towards A1, A2A-adenosine receptors was evaluated by radioligand receptor binding assays. All compounds showed a greater affinity and selectivity towards the A1-adenosine receptor than theophylline. The compounds in which the n-proyl group is in 1-position of the xanthine nucleus and the pyridazinone system in 8-position is linked through a chain of two or four carbon atoms, showed the highest affinity and selectivity.

Effects of substituent size upon adenosine receptor A1/A2 affinity of some newly synthesised 8-cycloalkyl xanthines.

The activity of a series of 1,3-dipropyl-xanthines bearing C8-cycloalkyl substituents as antagonists at A1 and A2 adenosine receptors is examined. Pharmacological results showed that the size of the 8-substituent is an important feature for response in activity of such class of antagonists. Among compounds 3-8, the 2-norbornyl analog 6 showed the best A1/A2 selectivity. A new route for the synthesis of 8-alkyl-substituted xanthines is presented. This method, consisting of a direct alkylation of the imidazole moiety through a radical mechanism reaction, was shown to be a more convenient strategy in comparison with the commonly employed synthetic schemes.

In vitro evaluation of the potential antitumor activity of an N-acridyl-pentanoyloxypyridine-2-thione derivative.

The synthesis and in vitro evaluation of the antitumor activity of an N-acridyl-pentanoyloxypridine-2-thione derivative (APPT), hypothesized to act as a DNA-intercalating compound, are described. The compound showed dose-dependent antiproliferative activity against all of the tested murine and human tumor cell lines, as evaluated by using the tetrazolium-based colorimetric assay. In addition, a comparative evaluation of the cytotoxic property was performed also against primary cultures of normal bone marrow cells. The results demonstrated that APPT possesses preferential antitumor activity and is endowed with an in vitro therapeutic index very similar to those of well known DNA-binding anti-neoplastic compounds, such as daunorubicin (DNR) and amsacrine (mAMSA). Therefore, APPT can be considered to be a potential selective cytoreductive drug.

In vitro cytotoxic activity of an N-hydroxypyridine-2-thione derivative.

The in vitro antitumor activity of N-(1-adamantoyloxy)pyridine-2-thione (APT), an N-hydroxypyridine-2-thione derivative, was investigated against a panel of both murine and human tumor cell lines growing in vitro. To evaluate the cytotoxic activity of APT the MTT ((4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) in vitro assay was used, which is considered to have predictive value for drug chemosensitivity evaluation. The results demonstrate that APT has antitumor activity, thus confirming theoretical suppositions about its cytoreductive potential.