Development and screening of novel drugs (analgesics, anti-hypertensive, muscarinic agonists and antagonists) Pharmacological characterization of endomorphin derivatives as novel analgesic agents Endomorphin-1
(Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2 ) are
peptides isolated from the mammalian brain which bind to µ-opioid
receptors with high affinity and selectivity. Endomorphins, i.c.v. or
i.t. administered, display antinociceptive activity and appear to
relieve neuropathic pain, which is assumed to be less sensitive to
traditional opioid receptor agonists. We are investigating novel
endomorphin-1 analogues which are more resistant to enzymatic
hydrolysis than endomorphin-1 by receptor binding and signal
transduction analysis in in vitro cell models to ascertain that they
behave as a µ-opioid receptor agonist. Antinociceptive activity of
these compounds, administered peripherally, shows that they will be
extremely useful for exploring the pharmacological profile of
endomorphins in vivo and confirms the potential therapeutic interest of
endomorphin derivatives as novel analgesic agents. Pharmacological characterization of calcium antagonists as novel cardiac drugs Synthesis,
characterization, and functional in vitro assays in cardiac tissues and
smooth muscle (vascular and nonvascular) of a several 4-imidazo[2,1-
b]thiazole-1,4-dihydropyridines: binding properties for the novel
compounds have been investigated and the interaction with the binding
site common to other aryl-dihydropyridines has been demonstrated.
Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium
channel blockers with a peculiar pharmacological behavior. Indeed, the
imidazo[2,1- b]thiazole system is found to confer to the
dihydropyridine scaffold an inotropic and/or chronotropic
cardiovascular activity with a high selectivity toward the nonvascular
tissue. Finally, molecular modeling studies were undertaken for the
most representative compounds with the aim of describing the binding
properties of the new ligands at molecular level and to rationalize the
found structure-activity relationship data. Due to the observed
pharmacological behavior of our compounds, they might be promising
agents for the treatment of specific cardiovascular pathologies such as
cardiac hypertrophy and ischemia.
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