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Allosteric Effects of the Alkane‐bis‐ammonium Compound W84 and of Tacrine on [ 3 H]Pirenzepine Binding at M 1 ‐Receptors in Rat Cerebral Cortex

1994; Wiley; Volume: 75; Issue: 6 Linguagem: Inglês

10.1111/j.1600-0773.1994.tb00380.x

1600-0773

Klaus Mohr, Christian Tränkle,

Lipid Membrane Structure and Behavior

The bis-quaternary W84, hexamethylene-bis-[dimethyl-(3-phthalimidopropyl)-ammonium bromide], is a potent allosteric modulator of M2-cholinoceptors. In this study we aimed at quantifying its allosteric effect on the dissociation of [3H]pirenzepine from M1-cholinoceptors in rat cerebral cortex and to measure the effects on association and equilibrium binding of [3H]pirenzepine. For sake of comparison tacrine was included which is known to be a potent allosteric modulator of [3H]pirenzepine binding to M1-receptors. Under control conditions (3 mM MgHPO4, 50 mM Tris-HCl, pH 7.4, 23 degrees) [3H]pirenzepine binding was characterized by KD = 5 nM and Bmax = 965 fmol/mg membrane protein, the rate constants amounting to k+1 = 5.0 microM-1 x min-1 and k-1 = 0.031 min-1. W84 and tacrine reduced [3H]pirenzepine binding concentration-dependently with IC50-values of 1.9 microM and 2.6 microM, respectively. [3H]pirenzepine association was inhibited by the compounds with EC50,ass = 1.8 microM for W84 and EC50,ass = 2.4 microM for tacrine. The concentrations reducing the dissociation rate by 50% amounted to EC50,diss = 21 microM for W84 and to EC50,diss = 54 microM for tacrine. Compared with W84, the dose-reponse curves of tacrine for the investigated effects were significantly steeper. In conclusion, WS84 affected [3H]pirenzepine binding to M1-receptors allosterically with a higher potency than tacrine but probably by a different mechanism.