Giuseppe Saccomanni

Synthesis and β-blocking activity of (R, S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine : potential antihypertensive agents - Part IX

The synthesis of oximeethers of 2,3-dihydro-1,8-naphthyridine and 2, 3-dihydrothiopyrano[2,3-b]pyridine is described. These compounds exhibit a selective beta-blocking activity, with a selectivity towards beta(2)-receptors. Groups in the N(1) position giving rise to a considerable steric hindrance led to a higher beta(2)-blocking selectivity, whereas groups creating a moderate hindrance caused a weak but significant decrease in beta(2)-antagonist potency. Substitution of the N(1)-R group with a sulfur atom led to compounds possessing beta(1)-, beta(2)- and beta(3)-blocking properties. Compounds 9c(1) and 10a(1) showed a beta(3)-antagonist activity slightly lower than that of propranolol.

Microfluidic approach for fast labeling optimization and dose-on-demand implementation

INTRODUCTION The diffusion of PET as a pivotal molecular imaging modality has emphasized the need for new positron-emitting radiotracers to be used in diagnostic applications and research. Microfluidic represents an innovative approach, owing to its potential to increase radiochemical productivity in terms of yields, time reduction, precursor consumption and flexible experimental planning. METHODS We focused on fluorine-18 labeling and used a microfluidic platform to perform sequential reactions, by using the same batch of (18)F-labeling solution on one or more substrates, during the same experimental session. A solid-phase extraction (SPE) workup procedure was also implemented in the system to provide a repeatable purification step. RESULTS We were able to quickly optimize the conditions for labeling of ethyl and propyl ditosylate and of a new cannabinoid type 2 (CB2) receptor agonist, CB41. In all substrates, we obtained good incorporation yields (60% to 85%) in short (<90 s) reaction times. Single dosages of the CB2 ligand were sequentially prepared, upon request, in satisfactory quantities and purity for small animal PET scanning. CONCLUSION This work demonstrates the usefulness of a microfluidic-based system for a rapid optimization of temperature, flow rate of reactants and their relative ratio in the labeling of different precursors by using the same (18)F-fluoride batch. This approach was used to obtain in sequence several injectable doses of a novel CB2 ligand, thus providing the proof of principle that microfluidic systems permit a dose-on-demand production of new radiotracers.

Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study.

The study evaluated the pharmacokinetics of tramadol and its major metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2) and N-O didesmethyltramadol (M5) following a single oral administration of a sustained release (SR) 100mg tablet to dogs. Plasma tramadol concentration was greater than the limit of quantification (LOQ) in three dogs, M1 was quantified only in one dog while M2 and M5 were quantified in all of the dogs. The median values of C(max) (maximum plasma concentration), T(max) (time to maximum plasma concentration) and T(1/2) (half-life) for tramadol were 0.04 (0.17-0.02)mirog mL(-1), 3 (4-2) and 1.88 (2.211-1.435)h, respectively. M5 showed median values of C(max), T(max) and T(1/2) of 0.1 (0.19-0.09)microg mL(-1), 2 (3-1) and 4.230 (6.583-1.847)h, respectively. M2 showed median values of C(max), T(max) and T(1/2) of 0.22 (0.330-0.080)microg mL(-1), 4 (7-3) and 4.487 (6.395-1.563)h, respectively. The findings suggest that the SR formulation of tramadol may not have suitable pharmacokinetic characteristics to be administered once-a-day as an effective and safe treatment for pain in the dog.

Synthesis of 1,8-naphthyridine derivatives: potential antihypertensive agents – Part VIII

A series of 2-(carbethoxypiperazinyl)- and 2-piperazinyl-1,8-naphthyridine derivatives, variously substituted, have been synthesized and pharmacologically investigated for their antihypertensive activity. Some of them exhibited a significant and prolonged decrease of the mean arterial pressure (MAP) on spontaneously hypertensive rats. For this series of compounds, on the basis of the pharmacological results obtained, no structure-activity relationship can be deduced at this time. Moreover, the most active and representative compounds 11b, 12a and 16b were investigated by means of in vitro pharmacological functional studies and in vivo, as diuretic agents, to determine a possible mechanism of the antihypertensive activity, which is unknown for the moment.

Synthesis and evaluation of antimycobacterial activity of 4-phenyl-1,8-naphthyridine derivatives.

Some 4-phenyl-1,8-naphthyridine derivatives with a piperazino group in the 2- and/or 7-position have been synthesized and evaluated for their tuberculostatic activity. The compounds 1, 6, 10, 17b,c and 19i showed a marked activity against Mycobacterium tuberculosis H37Rv. For this series of compounds, submitted to biological screening, no structure-activity relationship can be deduced.

Pharmacokinetics of tramadol and its major metabolites following rectal and intravenous administration in dogs

Abstract AIM: To compare the rectal and I/V administration of tramadol in dogs, to assess both its pharmacokinetic properties and absolute bioavailability. METHODS: After rectal administration via suppositories and I/V injection of tramadol (4 mg/kg), the concentration of tramadol and its main metabolites, O-desmethyl-tramadol (M1), N-desmethyl-tramadol (M2) and N,O-didesmethyl-tramadol (M5), were determined in plasma, using high-performance liquid chromatography (HPLC). A balanced cross-over study was used, involving six male Beagle dogs. RESULTS: Plasma concentrations after rectal and I/V administration were fitted on the basis of mono- and bi-compartmental models, respectively. Following rectal administration tramadol was detected from 5 minutes up to 10 hours, in lesser amounts than M5 and M2, while M1 was detected in negligible amounts. Following I/V administration tramadol was detected up to 10 hours, M2 and M5 were detected at similar concentrations, and M1 was present at low concentrations. The area under the curve (AUC) of the three metabolites did not differ significantly after either route of administration of tramadol. The absolute bioavailability of tramadol via rectal administration was 10 (SD 4)%. CONCLUSIONS: After rectal administration of tramadol suppositories, absorption of the active ingredient was rapid, but its metabolism quickly transformed the parent drug to high levels of M2 and M5. CLINICAL RELEVANCE: In the dog, rectal pharmaceutical formulation of tramadol would have a different pharmacokinetic behaviour than in humans.

Biopharmaceutical profile of tramadol in the dog

Biopharmaceutical profile of tramadol in the dog M. Giorgi & S. Del Carlo & G. Saccomanni & B. Łebkowska-Wieruszewska & V. Turini & C. Kowalski Published online: 8 July 2009 # Springer Science + Business Media B.V. 2009

Evaluation of tramadol and its main metabolites in horse plasma by high-performance liquid chromatography/fluorescence and liquid chromatography/electrospray ionization tandem mass spectrometry techniques

Tramadol is a centrally acting analgesic drug that has been used clinically for the last two decades to treat pain in humans. The clinical response of tramadol is strictly correlated to its metabolism, because of the different analgesic activity of its metabolites. O-Desmethyltramadol (M1), its major active metabolite, is 200 times more potent at the micro-receptor than the parent drug. In recent years tramadol has been widely introduced in veterinary medicine but its use has been questioned in some species. The aim of the present study was to develop a new sensible method to detect the whole metabolic profile of the drug in horses, through plasma analyses by high-performance liquid chromatography (HPLC) coupled with fluorimetric (FL) and photodiode array electrospray ionization mass spectrometric (PDA-ESI-MS) detection, after its sustained release by oral administration (5 mg/kg). In HPLC/FL experiments the comparison of the horse plasma chromatogram profile with that of a standard mixture suggested the identification of the major peaks as tramadol and its metabolites M1 and N,O-desmethyltramadol (M5). LC/PDA-ESI-MS/MS analysis confirmed the results obtained by HPLC/FL and also provided the identification of two more metabolites, N-desmethyltramadol (M2), and N,N-didesmethyltramadol (M3). Another metabolite, M6, was also detected and identified. The present findings demonstrate the usefulness and the advantage of LC/ESI-MS/MS techniques in a search for tramadol metabolites in horse plasma samples.

Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists.

The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.

Synthesis and antiplatelet activity of some 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives

Several 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid, collagen and ADP. Only five compounds showed any appreciable activity, and the results of all the active derivatives were similar to those of papaverine in the test with arachidonic acid and collagen. Moreover, the most active compounds were investigated in the test with ADP and again showed a significant activity. The tested compounds that possessed the best activity were also shown to increase the c-AMP level significantly without involving the adenylyl cyclase system.