NEW DERIVATIVES PIRRÓLICOS AND PIRAZÓLICOS, SYNTHESIS AND EVALUATION BIOLOGICAL VERSUS NITRIC OXIDE SYNTHASE.Author:
LÓPEZ CARA LUISA CARLOTA.
Year:
2004.
University:
GRANADA [
www.ugr.es].
Place of defense: FACULTAD DE FARMACIA.
Place of preparation: FACULTAD DE FARMACIA.
Summary: The neurodegeneration and neuronal death are commonalities in neurological disorders such as Alzheimer's disease, Parkinson's wrong, amyotrophic lateral sclerosis or Huntington's disease. Among the proposed molecular mechanisms leading to neuronal death highlights the increase of intracellular calcium, particularly in the case of glutamate neurotoxicity measure, which leads to disastrous consequences through the activation of intracellular protests, lipase, nucleaasa and activation of the enzyme oxide nitríco synthase (NOS), which catalyzes the formation of nitric oxide (NO), both forms constituent (or endothelial NOS and neuronal or NOS) and inducible (NOS). Currently, the antagonists of receptos glutamate under investigation in the hope of finding therapeutic agents targeted to ayden to combat neurodegeneration. However, since the mechanisms involved inthe neurotoxicidda currently proposed are very numerous and interconnected, it is considered essential for the development of new drugs exert their effects on common sites of the crucial and complicated cascade neurotoxic to show a neuroprotection effective. Research and development of agents aficaces against neurodegeneration involves the synthesis of new drugs that interfere somewhere in the complex chemical signaling d ela which the NOS, including inhibition of the enzyme itself is responsible for the synthesis of NO from L-arginine envarios cell types. Although NO is involved in synaptic transmission in a normal fashion, excessive levels of NO can be neurotoxic. The most important evidence of involvement of NO in neural toxicity comes from the neurotoxicity glutamatergic, through NMDA receptors. This neuronal toxicity can also play a crucial role in neurodegenerative diseases. Presumably, the activation of NMDA receptors and the subsequent increase in intracellular calcium levels, sde, initiate most forms of glutamatergic neurotoxicity. This type of toxicity implies NOT since treatment with inhibitors of NOS, the elimination of arginine environment, or the presence of reduced hemoglobin, blocking this form of neurotoxicity. While nitric oxide is required under physiological conditions, production me to be regulated. Excessive release of gultamato acting on NMDA receptors, causing an increase of inflow of calcium ions into the cells, resulting in the formation of NO by the NOS through a mechanism dependent calcio-calmodulina. NO acts as a messenger retrograde being a free radio, has many target molecules from which to start the cascade of neurotoxicity. Our group, research has found and described the hormone melatonin shows a latency period between two four in his attenuator effect of stimulus glutamatérgico measured by the technique of electrosifología. This could latency between two four in his attenuator effect of stimulus glutamatérmico, medium through technical lelctrofisiología. This could be interpreted ausmiendo that melatonin requires a metabolic activation, as measured meidante technique lectrofisiologíca. This could be interpreted by assuming that the brain metabolite, which acts as sort endogenous active. It has also prepared derivative structure kinurenínica which attenuate stimulating cytotoxic produced by glutamate more power than the melatonin Woe perído without latency. Ad 8 emás at 75e gunos compounds are able to inhibit NOS concentrations near nanomolar. In search of new neuroprotective drugs via inhibition of NOS, have prepared a series of derivatives Kinurenaminas structures aril pirazolinica that if more structures are equally rigid geometries can also adopt similar to the analogue linear chain, debidop to it facilitates the formation of a link between hydrogen nitrogen imínico of pirazolina and the aromatic amino group. It has studied the effect of these compounds on the activity of NOS estriado rat, we found that all of them inhibit the activity of the enzyme. In this PhD thesis summarizes a total of 22 structured compounds fenilipirrólica, 10 structure benzoilpizalínica and 11 with structure benzoilpirazólica. All of them are being tested as inhibitors of NOS NOS and found that fenilpirroles are the best NOS inhibitors while, the NOS is preferentially inhibited by compounds structures benzoilpirazólica. The investigation should be continued in order to obtain more data inhibition of NOS and enhance the activity of the compounds obtained.
