Allosteric modulators and selective agonists of muscarinic receptors.

Ulrike Holzgrabe, Marco De Amici, Klaus Mohr

Index: J. Mol. Neurosci. 30(1-2) , 165-8, (2006)

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Abstract

Allosteric modulators of ligand-receptor interactions are found for a variety of receptors (Christopoulos, 2002). Allosteric agents attach to a binding site being topographically distinct from the site for conventional (orthosteric) agonists or antagonists. In the case of the muscarinic receptor, a huge selection of structurally divergent modulators has been described for different receptor subtypes (Mohr et al., 2003). Alkane-bisammonio-type compounds carrying lateral phthalimido substituents are known to have a high affinity for the common allosteric binding site of the muscarinic acetylcholine M2 receptor (mAChR M2), which is already occupied by the orthosteric antagonist N-methylscopolamine (NMS). The resulting allosteric inhibition of the dissociation of [3H]NMS from the M2 receptors in porcine cardiac homogenates served to indicate binding of the test compounds to the allosteric site. Additionally, allosteric modulators can strongly influence equilibrium binding of the orthosteric ligand: Its binding can be reduced, left unaltered or elevated, and encoded as negative, neutral, and positive cooperativity, respectively (Christopoulos and Kenakin, 2002). The cooperativity is strongly dependent on the pair of allosteric/orthosteric ligands and on the receptor subtype.