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Some antagonists exhibit tissue selectivity in their pharmacological antagonism of muscarinic responses. However, the affinity constants for equilibrium binding of classical antagonists to muscarinic receptors in subcellular preparations have shown only small variations in different peripheral tissues and regions of the brain. The binding curves do not(More)
Current antipsychotics provide symptomatic relief for patients suffering from schizophrenia and related psychoses; however, their effectiveness is variable and many patients discontinue treatment due to side effects. Although the etiology of schizophrenia is still unclear, a leading hypothesis implicates an imbalanced dopaminergic system. Muscarinic(More)
In an attempt to locate the allosteric site on muscarinic receptors to which gallamine binds, 21 residues in the putative external loops and loop/transmembrane helix interfaces have been mutated to alanine. These residues are conserved in mammalian m1-m5 receptors. All mutant receptors can be expressed in COS-7 cells at high levels and appear to be(More)
The distribution of muscarinic receptors has been studied in the rat midbrain and hindbrain by counting silver grains in light microscope autoradiographs of the specific (atropine-sensitive) binding of [3H]propylbenzilylcholine mustard in cryostat sections. Of the 78 areas studied 6 had grain counts between 6 and 9 times the nonspecific level ("high"), and(More)
The binding characteristics of muscarinic receptors have been critically examined in six regions of the rat brain. The binding curves of antagonists are similar for all six areas but the binding curves of agonists show large differences. It is shown that in all regions there are three classes of receptors with similar binding characteristics but that these(More)
Thiochrome (2,7-dimethyl-5H-thiachromine-8-ethanol), an oxidation product and metabolite of thiamine, has little effect on the equilibrium binding of l-[3H]N-methyl scopolamine ([3H]NMS) to the five human muscarinic receptor subtypes (M1-M5) at concentrations up to 0.3 mM. In contrast, it inhibits [3H]NMS dissociation from M1 to M4 receptors at(More)
1. The estimation of antagonist affinity from functional experiments in which the effect of a fixed agonist concentration is reduced by a range of antagonist concentrations ('functional inhibition curves') has been considered from both a theoretical and experimental viewpoint. 2. Theoretical predictions are compared with results obtained from the(More)
We have studied the interactions of five indolocarbazoles with N-[methyl-(3)H]scopolamine (NMS) and unlabeled acetylcholine at M(1)-M(4) muscarinic receptors, using equilibrium and nonequilibrium radioligand binding studies. The results are consistent with an allosteric model in which the primary and allosteric ligands bind simultaneously to the receptor(More)
The ternary allosteric model predicts the possibility of discovering molecules with novel and highly subtype-selective modes of action. This approach has been applied to muscarinic receptors. The alkaloid brucine is capable of selectively enhancing by an allosteric mechanism the effects of low but not high concentrations of acetylcholine at only the m1(More)