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.