Tacrine (THA) selectively modulates binding of M1 ligands in an allosteric fashion causing positive cooperativity. The binding affinity of THA to M1 and M2 cholinoceptors is similar. It is therefore proposed that the allosteric selectivity of THA is a function of the binding site and not of THA itself. Its interaction of M1 and M2 cholinoceptors was examined in guinea pig brain homogenates using the selective M1 and M2 antagonists [3H]-pirenzepine ([3H]PZ) and [3H]AF-DX 384. The dissociation constants were 0.36 nmol/l for the M1 receptor and 0.23 nmol/l for the M2 receptor. We also compared the binding of THA and methoctramine (MTA) at M2 receptors. Tacrine displayed similar binding affinity for both M1 and M2 receptor subtypes. MTA was 100 times more potent an inhibitor of [3H]AF-DX 384 binding at M2 receptors than THA. In addition, THA was found to slow the dissociation of [3H]PZ from the M1 receptor. In contrast, the dissociation of [3H]AF-DX 384 from M2 receptor subtypes was unaffected. We conclude that THA acts as an agonist at M1 cholinoceptors because it slowed the dissociation of [3H]PZ. At M2 cholinoceptors its nature is that of an antagonist because it had no effect on [3H]AF-DX 384 dissociation.

Keywords:
Tacrine, Cholinoceptors, M1 and M2
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© 1993 S. Karger AG, Basel
1993
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