Galactosylated dopamine enters into the brain, blocks the mesocorticolimbic system and modulates activity and scanning time in Naples high excitability rats.

Pathological conditions, such as Parkinson's disease and attention deficit hyperactivity disorder, have been linked to alterations of specific dopamine (DA) pathways. However, since exogenous DA does not cross the blood-brain barrier, DA levels can be modulated e.g. by DA precursors or DA reuptake blockers. Hereby histochemical, analytical and behavioral evidence shows that a galactosylated form of DA (GAL-DA) carries DA into the brain, thus modulating activity and nonselective attention in rats. To this aim adult male rats of the Naples high-excitability (NHE) and random bred controls (NRB) lines were given a single i.p. injection of GAL-DA (10 or 100 mg/kg). Three hours later the behavior was videotaped and analyzed for horizontal activity, orienting frequency and scanning duration. The dose of 100 mglkg of GAL-DA reduced by 25% the horizontal activity in NHE rats, mainly in the first part of the testing period. No effect was observed on orienting frequency or on scanning duration. However, GAL-DA 100 mg/kg was associated with longer rearing episodes in the second part of the testing period in NHE rats. In parallel experiments histochemistry with a galactose-specific lectin showed 10% increase in galactose residues into the striatum between 0.5 and 3.0 h. To quantify the level of GAL-DA, its metabolite DA-succinate and DA in the prefrontal cortex, neostriatum, and cerebellum, rats were killed 2.0 h after the injection of prodrug. Mass high performance liquid chromatography (HPLC) was used for analysis of GAL-DA and DA succinate whereas electrochemical HPLC for DA. Both HPLC techniques demonstrate that GAL-DA carries and releases DA into the brain. Specifically 100 mg/kg of GAL-DA increased DA level in the striatum in the NHE rats only. Moreover, DA in the mesencephalon (MES) was correlated positively with striatal and prefrontal cortex DA in NHE rats. In contrast DA in the MES was negatively correlated with striatal DA in NRB. GAL-DA disrupted these correlations in both rat lines. Thus, this new DA prodrug may modify DA neurotransmission and might have a potential clinical application.

Research on heterocyclic compounds, XLI. 2-Phenylimidazo

The synthesis of a group of 2-phenylimidazo[1,2-b]pyridazine-3-acetic esters and acids is described. The structures of the new compounds are supported by 1H-NMR spectra. These compounds were tested in vivo for their anti-inflammatory, analgesic and ulcerogenic activity. All new compounds showed remarkable anti-inflammatory action in the carrageenan rat paw oedema (one third of that for indomethacin) but no significant analgesic activity in the acetic acid writhing test together with negligible ulcerogenic action, and were also found to be lacking inhibitory activity on cyclooxygenase in vitro.

Research on heterocyclic compounds, Part 40. 2-Phenylimidazo[1,2-a]pyridine-3-carboxylic acid derivatives: synthesis and antiinflammatory activity.

A series of 2-phenylimidazo[1,2-a]pyridine-3-carboxylic esters, acids, and amides were synthesized and pharmacologically tested in order to evaluate their antiinflammatory and analgesic activity and their ulcerogenic action on the gastro-intestinal tract. The most active member of this series of compounds was found to be 6-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (5c).

Research on heterocyclic compounds. XXXVIII. Synthesis and pharmacological activity of imidazo[1,2-b]pyridazine-2-carboxylic derivatives.

A series of imidazo[1,2-b]pyridazine-2-carboxylic acids, esters and amides was synthesized and tested for antiinflammatory, analgesic and ulcerogenic activities. The ethyl esters were prepared by cyclocondensation of some 3-aminopyridazines with ethyl bromopyruvate, followed by hydrolysis or ammonolysis in order to obtain the corresponding acids and amides. The inhibitory activity on the carrageenan-induced edema in the rat paw and on writhes induced by acetic acid in mice was evaluated, as well as the ulcerogenic action on the rat gastric mucosa. The pharmacological activity was discussed in terms of structure-activity relationships. In particular, the analgestic activity shown by these carboxylic derivatives was compared with that found in other series of imidazo[1,2-b]pyridazine analogues previously examined.

Research on heterocyclic compounds. XXXIII--Synthesis and analgesic activity of imidazo[1,2-b]pyridazine-2-acetic acid derivatives.

A series of imidazo[1,2-b]pyridazine-2-acetic esters, acids and amides was synthesized and tested for antiinflammatory, analgesic and ulcerogenic activities. The ethyl esters were prepared by cyclocondensation of some 3-aminopyridazines with ethyl 4-chloroacetoacetate, followed by hydrolysis or ammonolysis in order to obtain the corresponding acids and amides. The capacity of inhibiting the carrageenan-induced edema in the rat paw and the writhes induced by acetic acid in mice were evaluated, as well as the ulcerogenic action in rats. The acidic derivatives showed significant analgesic activity which is comparable to that found in other series of imidazo[1,2-b]pyridazine analogs previously examined.

Research on heterocyclic compounds, XXIX. Synthesis and antiinflammatory activity of imidazo[1,2-a]pyrazine derivatives.

The reaction in anhydrous ethanol of some substituted 2-aminopyrazines with ethyl 2-benzoyl-2-bromoacetate or with ethyl 3-bromo-4-oxopentanoate afforded a group of ethyl 2-phenylimidazo[1,2-a]pyrazine-3-carboxylates and a group of ethyl 2-methylimidazo[1,2-a]pyrazine-3-acetates, respectively. The corresponding acids obtained via alkaline hydrolysis were subjected to pharmacological testing in vivo in order to evaluate their antiinflammatory activity.

Research on heterocyclic compounds. XXX. Synthesis and pharmacological activity of 2-methylimidazo[1,2-b]pyridazine-3-carboxylic acids.

A group of ethyl 2-methylimidazo[1,2-b]pyridazine-3-carboxylates were prepared by reaction in anhydrous ethanol of some substituted 3-amino-pyridazines with ethyl 2-chloroacetoacetate. The corresponding carboxylic acids were obtained via alkaline or acid hydrolysis and then tested both in vivo to evaluate their antiinflammatory, analgesic and ulcerogenic actions and in vitro for their ability to inhibit the prostaglandin biosynthesis. The pharmacological results are discussed in terms of both structure-activity relationships and mechanism of action.

Research on heterocyclic compounds. XXVIII. Imidazo[1,2-c]pyrimidines.

A group of 24 imidazo[1,2-c]pyrimidines was taken into consideration in order to study their relationships between chemical structure and antiinflammatory activity. Some of these compounds were synthesized by us in the past, the others have been synthesized and characterized to complete the series. Antiinflammatory, analgesic, antipyretic and gastric ulcerogenic activities of such compounds were compared with those of indomethacin and discussed in terms of the effects exerted by the presence on the heterocyclic system of various substituents and an acidic or nonacidic moiety.

Research on heterocyclic compounds. XXVII. Synthesis and antiinflammatory activity of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acids.

A group of ethyl esters of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acids 3 were obtained by reaction in anhydrous ethanol of some substituted 3-aminopyridazines 1 with ethyl 2-benzoyl-2-bromoacetate 2. The acids 4 obtained via alkaline hydrolysis were tested in vivo for their antiinflammatory, analgesic and ulcerogenic actions and in vitro for their ability to inhibit the prostaglandin biosynthesis. Almost all of the new compounds showed high analgesic activity, whereas the activities exhibited in the other tests were sharply lower. These results are discussed in terms of mechanism of action.

Research on heterocyclic compounds. XXVI. Antiinflammatory and related activities of some 2-phenylimidazo[1,2-b]pyridazines.

Five acidic phenyl derivatives of the imidazo[1,2-b]pyridazine system were subjected to some tests in vivo in order to evaluate their biological activity. Antiinflammatory activity was studied by means of the carrageenin rat paw edema, whereas writhing induced in mice by acetic acid was used to assess analgesic activity. The irritative and ulcerogenic action on the rat gastric mucosa was examined after oral administration of larger doses. The inhibitory activity on platelet malondialdehyde production was studied in vitro. The experimental results are discussed from the point of view of structure-activity relationships and mode of action.

Research on heterocyclic compounds. XXV. Phenyl derivatives of fused imidazole systems: antiinflammatory activity.

A group of seven acidic phenyl derivatives of some fused imidazole systems were subjected to a series of tests in vivo in order to evaluate their pharmacological activity. Antiinflammatory activity was studied by means of the carrageenin-induced rat paw edema. Hot plate test and writhing induced by acetic acid in mice were used to evaluate analgesic activity. Yeast-induced hyperthermia in rats was employed to study antipyretic action. Irritative and ulcerogenic action on the rat gastric mucosa was examined at higher doses. The antiaggregating activity and the inhibition of platelet malondialdehyde production were studied in vitro. All experimental results are discussed from the point of view of structure-activity relationships and mode of action.

Research on heterocyclic compounds. XXIV. Antiinflammatory activity of some imidazo[1,2-c]pyrimidine derivatives.

A group of four acidic imidazo[1,2-c]pyrimidine derivatives were subjected to a series of tests in vivo in order to assess their pharmacological activity. Antiinflammatory activity was studied by means of the carrageenin-induced paw edema and pleurisy in rats. Hot plate test and writhing induced by acetic acid in mice were employed to evaluate analgesic activity, whereas the yeast-induced hyperthermia in rats was used to study antipyretic activity. The irritative and ulcerogenic action on the rat gastric mucosa was examined at higher doses. The inhibitory activity on the platelet malondialdehyde production was studied in order to obtain information about the mechanism of action of test compounds.

Research on heterocyclic compounds. XXII. Imidazo[1,2-a]pyrimidines.

We have taken into consideration a group of 21 imidazo [1,2-a]pyrimidine derivatives, some of which were already known, whereas the others were synthesized and characterized by us to complete the series. Antiinflammatory, analgesic, antipyretic and ulcerogenic activities of such compounds were evaluated in comparison with indomethacin, in order to get useful information about structure-activity relationships.

Research on heterocyclic compounds. XIX--2-Methylimidazo[1,2-a]pyridine-3-acetic acids.

A group of methyl substituted imidazo[1,2-a]pyridine-3-acetic acids was synthesized by reaction of some methyl derivatives of 2-aminopyridine with ethyl 3-bromolevulinate and subsequent hydrolysis. These new acidic compounds were tested for their antiinflammatory, analgesic, antipyretic and ulcerogenic activities in order to compare the results with those previously obtained with similar compounds.

Research on heterocyclic compounds. XVIII. Imidazo[2,1-b]-1,3,4-thiadiazole derivatives.

The synthesis of a series of 6-carbethoxy-, 6-carbethoxy-methyl-, and 5-carbethoxy-6-methylimidazo[2,1-b]-1,3,4-thiadiazoles was accomplished by reacting some 2-amino-1,3,4-thiadiazoles with ethyl bromopyruvate, 4-chloroacetoacetate, and 2-chloroacetoacetate, respectively; such carbethoxy derivatives afforded the corresponding carboxylic acids by hydrolysis. The antiinflammatory, analgesic, antipyretic and ulcerogenic activities were studied on three of the new acidic compounds.

Research on heterocyclic compounds. XVII. 2-Methylimidazo[1,2-a]pyrimidine-3-carboxylic acids.

A group of ethyl 2-methylimidazo[1,2-a]pyrimidine-3-carboxylates were prepared by reaction of ethyl 2-chloroacetoacetate with some 2-aminopyrimidines. These ethyl esters were then converted into the corresponding carboxylic acids via alkaline hydrolysis. The acids so obtained were evaluated for antiinflammatory, analgesic, antipyretic and ulcerogenic activities.

Research on heterocyclic compounds. XV. Substitution influence on the pharmacological activity in a series of imidazo[1,2-a]pyridines.

We have taken into consideration a group of 28 imidazo [1,2-a]pyridine derivatives, some of which were already known, whereas the others have been synthesized and characterized to complete the series. Antiinflammatory, analgesic, antipyretic and ulcerogenic activities of such compounds were evaluated in comparison with indomethacin. The pharmacological data demonstrated the effects exerted on activity by the presence on the heterocyclic system of methyl substituents and/or an acidic moiety.

Research on heterocyclic compounds. XIV - Imidazothiazole and imidazobenzothiazole derivatives: synthesis and antiinflammatory activity.

A group of ethyl 6-methylimidazo[2,1-b]thiazole-5-carboxylates and 2-methylimidazo[2,1-b]benzothiazole-3-carboxylates was prepared by reaction of ethyl 2-chloroacetoacetate with some 2-aminothiazoles and 2-aminobenzothiazoles, respectively. Such reactions may sometimes afford a side product which was isolated and characterized. The ethyl esters were then converted into the corresponding acids by hydrolysis. Three of these acids were evaluated for antiinflammatory, analgesic, and antipyretic activities, as well as for ulcerogenic potential.