ABSTRACT
Ion-channel blockers are molecules that obstruct the path used by ions to cross the membrane through a protein channel. Many of these are local anesthetics, toxins or drugs of abuse, and the knowledge of their mechanism of action at the atomic level is an important step towards the development of new compounds on a structural basis. A molecular model of the transmembrane region of the nicotinic acetylcholine receptor, an important brain and muscle fast signaling protein, was used as a target for docking several channel blockers by means of an automatic docking method. The combination of the independent docking method and molecular models (of the receptor and blockers) reproduced or explained quite accurately experimental data (photoaffinity labeling, site-directed mutagenesis, binding assays). This represents a strong support for the validity of the predictions made for those molecules for which no experimental data is available and also for the models and methods on which are based.
Subject(s)
Lidocaine/analogs & derivatives , Nicotinic Antagonists/pharmacology , Proadifen/analogs & derivatives , Receptors, Nicotinic/metabolism , Acetylcholine/metabolism , Acetylcholine/pharmacology , Animals , Binding Sites , Chlorisondamine/metabolism , Chlorisondamine/pharmacology , Ethidium/metabolism , Ethidium/pharmacology , Hexamethonium/metabolism , Hexamethonium/pharmacology , Lidocaine/metabolism , Lidocaine/pharmacology , Mice , Nicotinic Antagonists/metabolism , Onium Compounds/metabolism , Onium Compounds/pharmacology , Pempidine/metabolism , Pempidine/pharmacology , Proadifen/metabolism , Proadifen/pharmacology , Quinacrine/metabolism , Quinacrine/pharmacology , Trityl Compounds/metabolism , Trityl Compounds/pharmacologyABSTRACT
Adrenal enkephalin and enkephalin-containing peptides were studied during postnatal development in normotensive (WKY) and spontaneously hypertensive rats (SHR). The effect of chronic treatment with the ganglionic blocker chlorisondamine (5 mg/kg) was also assessed. Free enkephalin immunoreactivity and total enkephalin immunoreactivity, as determined by enzymatic digestion of large enkephalin containing fragments, were quantitated in the adrenal glands at 11 days and 7, 16, and 24 weeks of age. Both total and free metenkephalin were significantly diminished in the adrenal of SHR when compared to WKY at all ages tested. The analysis of the chromatographic profile showed that SHR displayed reduced levels of high and low molecular weight materials at 11 days and 16 weeks of age; however intermediate compounds were high in the glands of these animals. Similar increased values for free met-enkephalin were found in adrenals of WKY and SHR after ganglionic blocker treatment, which means that the relative increase was larger in SHR than WKY; while for total enkephalin the relative increase and the concentration reached in SHR was about half of those presented in WKY. These and other results presented suggest that the basic alteration of the adrenal proenkephalin system of SHR may be due to a genetic reduction of proenkephalin levels. Otherwise, the free enkephalin decrease could be related to changes in nervous input to the adrenal gland.
Subject(s)
Adrenal Glands/metabolism , Aging/metabolism , Enkephalins/metabolism , Hypertension/metabolism , Protein Precursors/metabolism , Adrenal Glands/drug effects , Animals , Chlorisondamine/pharmacology , Chromatography, Gel , Enkephalin, Leucine/metabolism , Enkephalin, Methionine/metabolism , Male , Molecular Weight , Rats , Rats, Inbred SHR , Rats, Inbred WKYABSTRACT
The role of nicotinic cholinergic transmission in cold stress-induced alterations in rat adrenomedullary tyrosine hydroxylase (TH) mRNA was investigated by RNA dot-blot hybridization, using a cloned TH cDNA probe. Chlorisondamine, a ganglionic blocking agent, greatly attenuated the induction of TH mRNA levels caused by cold exposure, whereas carbachol and nicotine, cholinergic agonists, increased TH mRNA in control animals. These results suggest that cholinergic nicotinic receptors play a key role in the transsynaptic induction of adrenal TH gene expression.