Glycogen depletion and resynthesis during 14 days of chronic low-frequency stimulation of rabbit muscle.

Electro-stimulation alters muscle metabolism and the extent of this change depends on application intensity and duration. The effect of 14 days of chronic electro-stimulation on glycogen turnover and on the regulation of glycogen synthase in fast-twitch muscle was studied. The results showed that macro- and proglycogen degrade simultaneously during the first hour of stimulation. After 3 h, the muscle showed net synthesis, with an increase in the proglycogen fraction. The glycogen content peaked after 4 days of stimulation, macroglycogen being the predominant fraction at that time. Glycogen synthase was determined during electro-stimulation. The activity of this enzyme was measured at low UDPG concentration with either high or low Glu-6-P content. Western blots were performed against glycogen synthase over a range of stimulation periods. Activation of this enzyme was maximum before the net synthesis of glycogen, partial during net synthesis, and low during late synthesis. These observations suggest that the more active, dephosphorylated and very low phosphorylated forms of glycogen synthase may participate in the first steps of glycogen resynthesis before net synthesis is observed, while partially phosphorylated forms are most active during glycogen elongation.

Synthesis and immunosuppressive activity of novel prodigiosin derivatives.

Prodigiosins (Ps) represent a family of naturally occurring red pigments characterized by a common pyrrolylpyrromethene skeleton. Some members of this family have been shown to possess interesting immunosuppressive properties exerted with a novel mechanism of action, different from that of currently used drugs. In fact, Ps inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with a cell surface receptor component called common gamma-chain, which is exclusive of all IL-2 cytokine family receptors. Blocking common gamma-chain transduction activity results in a potent and specific immunosuppressive activity. With respect to the interesting and unexploited immunomodulating properties of this family of compounds we initiated a medicinal chemistry program aimed at finding novel prodigiosin derivatives with improved immunosuppressive activity and lower toxicity. Utilizing an unprecedented and flexible way of assembling the prodigiosin frame, a number of new derivatives have been prepared and tested leading to the choice of 4-benzyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2, 2'-bi-1H-pyrrole (PNU-156804, 16) as a lead immunosuppressant.

Synthesis and immunomodulating activity of condensed N-aryl-2-cyano-3-oxo-3-pyrazolyl-propanamides.

A series of condensed N-aryl-2-cyano-3-oxo-3-pyrazolyl-propanamides were synthesized and evaluated for immunomodulating activity following intraperitoneal administration. These new molecules were found to enhance macrophage cytotoxicity and stimulate host mediated antibacterial defences in mice. The compound 3-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol- 3-yl]-3-oxo-N-phenyl-propanamide, chosen for wider pharmacological investigation, proved effective in preventing adjuvant-induced arthritis development in rats.

Synthesis and antiinflammatory activity of 5-oxo-5H-1,3,4- thiadiazolo[3,2-a]pyrimidine-6-carboxamides.

A series of 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-carboxamides were synthesized and evaluated for antiinflammatory activity in the carrageenin oedema test and in RPAR in the rat. Some proved active in both tests. Two compounds, namely 2-(3-pyridyl)- and 2-morpholino-5-oxo-5H- 1,3,4-thiadiazole[3,2-a]pyrimidine-6-N-(2-pyridyl)carboxamide were particularly interesting.

Synthesis and antiulcer activity of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo [1,5-a]pyrimidine-7-ones.

A series of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo-[1,5-a]pyrimidine-7-ones were synthesized and evaluated for the inhibition of stress-induced gastric ulcers in the rat after oral administration. Several molecules were found to be very active. The particularly interesting compound (E)-1-(3-chlorophenyl)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo[1,5-a]- pyrimidine-7-one was chosen for wider pharmacological investigation.

7-trans-(2-Pyridylethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-ones: synthesis and pharmacological activity.

A series of 7-trans-(2-pyridylethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-ones was synthesized and evaluated for their pharmacological activity. Some compounds were found to be effective in inhibiting restraint ulcers in the rat. Two of them also showed interesting antiinflammatory activity.

Synthesis and antiinflammatory activity of 7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-N-pyridylcarboxamides.

A series of 7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-N-pyridylcarboxamides was synthesized and assayed in the carrageenin-induced paw oedema test in the rat. Some compounds showed moderate antiinflammatory activity.

New derivatives of pyrrolo and pyrido[2,1-b] quinazoline as antiulcer agents.

A series of 3-benzylidene-1,2,3,9-tetrahydro-9-oxopyrrolo-[2,1-b] quinazolinecarboxylic acids and 6-benzylidene-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazolinecarboxylic acid was synthesized and evaluated for their antiulcer activity by the test of inhibition of restraint ulcers in the rat, and for gastric antisecretory activity using the technique of Shay. Some compounds appear potentially useful for therapeutic application.