Drugs online research references
Brain Res. 1986 Jan 8;362(2):239-53.
Muscarinic cholinergic receptor subtypes in the human brain. II. Quantitative autoradiographic studies.
Cortes R, Probst A, Tobler HJ, Palacios JM.
The distribution and characteristics of M1 and M2 muscarinic cholinergic receptors as defined by their affinity for the antagonist pirenzepine were studied in the human brain using in vitro quantitative autoradiographic techniques. The binding of N-[3H]methylscopolamine ([3H]NMS) to cortical and striatal microtome tissue sections was saturable and presented a Kd of 0.25 nM. The sensitivity of [3H]NMS-binding sites to 100 microM carbachol and 300 nM pirenzepine was analyzed in 30 brain areas. In selected brain regions, complete competition curves using carbachol, pirenzepine and atropine were analyzed. Finally, the regional distribution of M1 sites was studied using [3H]pirenzepine ([3H]PZ) as ligand. The binding of [3H]NMS to striatum, hippocampus and amygdala was very sensitive to pirenzepine but not to carbachol. The opposite situation was found in thalamus, hypothalamus, substantia innominata, pons and medulla, while intermediate sensitivity to both displacers was observed in different layers of the cortex and in the claustrum. Competition experiments showed that [3H]NMS binding was displaced with the same affinity by atropine in all the regions studied, while the IC50 of carbachol varied from 5 microM in the nucleus facialis to 830 microM in the caudate. Pirenzepine IC50 values for [3H]NMS sites varied from 66 nM to 1 microM. Results using [3H]PZ further confirm this pattern of distribution, with high densities of binding observed in the striatum, hippocampus and amygdala and very low in thalamic and brainstem areas. These results show that the putative M1 and M2 muscarinic receptor subtypes present a differential anatomical distribution in the human brain. This differential distribution is comparable to that observed in the rat brain. Some basal ganglia and limbic areas are enriched in M1 sites, while thalamus, brainstem, medulla and also the hypothalamus and substantia innominata contain predominantly receptors of the M2 type. The cerebral cortex is an example of a region containing a mixed population of M1 and M2 sites. These results provide an anatomical description of the distribution of subtypes of the muscarinic receptor in the human brain, which can be related to the known pharmacological effects of muscarinic agents in brain function.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3753655&dopt=Abstract
J Pharmacol Exp Ther. 1987 Jan;240(1):23-30.
Coupling of muscarinic receptors to adenylate cyclase in the rabbit myocardium: effects of receptor inactivation.
Ehlert FJ.
The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition was investigated in homogenates of the rabbit myocardium. The highly efficacious muscarinic agonist oxotremorine-M caused half-maximal inhibition of adenylate cyclase activity at a concentration (Ki) that was 10-fold smaller than that required for half-maximal receptor occupancy in the presence of 0.1 mM GTP (D50-GTP) as measured by competitive displacement of the binding [3H]N-methylscopolamine. In contrast, there was much closer agreement between the Ki and D50-GTP of the less efficacious oxotremorine analog BM5 [N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide]. By comparing equal levels of adenylate cyclase inhibition before and after partial inactivation of muscarinic receptors with benzilycholine mustard, it was possible to estimate the dissociation constants (KA) of the oxotremorine analogs. There was good agreement between KA and D50-GTP and also between the degree of receptor inactivation determined pharmacologyically and that estimated by measurements of the binding of [3H]N-methylscopolamine.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3806386&dopt=Abstract
Brain Res. 1986 Jan 8;362(2):227-38.
Muscarinic cholinergic receptor subtypes in the rat brain. I. Quantitative autoradiographic studies.
Cortes R, Palacios JM.
The binding characteristics of N[3H]methylscopolamine ([3H]NMS) to slide-mounted tissue sections were studied using quantitative autoradiography. Binding of [3H]NMS was saturable, reversible and of high affinity (Kd = 0.26 nM). The inhibition of [3H]NMS binding produced by several muscarinic agonists and antagonists was analyzed in 29 discrete brain regions by constructing complete displacement curves. Comparison of IC50 values obtained both biochemically and by autoradiography demonstrated a very close agreement, supporting the validity of the autoradiographic approach. The competition curves for the agonists carbachol, oxotremorine and 2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion-h ydrobromide (RS 86) fitted to a two-site model, with comparable affinity values from region to region, although different proportions of high- and low-affinity sites were seen in the different areas studied. The distribution of high- and low-affinity sites was similar for the three agonists. Atropine showed monophasic curves presenting similar affinities in all regions studied. In contrast, pirenzepine differentiated between high- and low-affinity sites which showed a distribution opposite to that observed for the agonists. Gallamine, a ligand for a putative regulatory site in the muscarinic receptor, inhibited [3H]NMS binding in a biphasic manner. The calculated IC50 values for the gallamine high- and low-affinity sites did not vary from region to region and the distribution of these sites correlated well with that observed for the agonists. High-affinity pirenzepine sites (also called M1 sites) were localized mainly in forebrain areas, such as striatum, hippocampus and cortex, and their regional distribution correlated with that of the low-affinity sites for the agonists and gallamine. On the other hand, low-affinity sites for pirenzepine (named M2 sites) were mainly found in the brainstem and parts of the thalamus. A good correlation was found between pirenzepine low-affinity sites and agonist and gallamine high-affinity sites. The significance of these findings is discussed in relation to the known and possible effects of selective M1 and M2 centrally acting agents.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3942874&dopt=Abstract
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