The pharmacological action of MT-7

The mamba toxin MT-7 is the most selective ligand currently available for the muscarinic M-1 receptor subtype. The toxin binds stably to the receptor and blocks the agonist-induced activation non-competitively. Although its mode of action on M-1 receptors is not yet fully understood, some of the toxin properties support an allosteric mechanism. Thus, the toxin fails to elicit a complete inhibition of the binding of either the muscarinic antagonist [H-3]N-methyl-scopolamine ([H-3]NMS) or the agonist [H-3]acetylcholine ([H-3]ACh). When added to ligand-occupied M-1 receptors, the toxin slows the dissociation rate of [H-3]NMS and increases that of [H-3]ACh. Site-directed mutagenesis studies have provided important information about the toxin amino acid residues which are critical for the stable binding to the receptor and for the allosteric modulation of antagonist dissociation. In vivo studies have shown that the intracerebral injection of MT-7 causes a long-lasting blockade of M-1 receptor, thus providing a tool for the characterization of the functional role of this receptor subtype in discrete brain areas. (C) 2004 Elsevier Inc. All rights reserved.