Opposite effects of alcuronium on agonist and on antagonist binding to muscarinic receptors

Alcuronium is known to retard allosterically the dissociation of [H-3]N-methylscopolamine from muscarinic M(2) receptors, thereby augmenting the binding of this antagonist. Functionally, alcuronium behaves as a weak antimuscarinic agent and induces in combination with N-methylscopolamine an overadditive antimuscarinic action with oxotremorine-M as the agonist. The effect of alcuronium on the binding of [H-3]oxotremorine-M was studied in porcine heart homogenates. Agonist binding was concentration dependently inhibited with a K-i = 0.48 +/- 0.03 mu M (means +/- S.D., n = 3). Under identical conditions [H-3]N-methylscopolamine binding was elevated. Alcuronium, 100 mu M, which nearly prevented the dissociation of [H-3]N-methylscopolamine, retarded the rate of dissociation of [H-3]oxotremorine-M only by a factor of two. These findings support the notion that the overadditive antimuscarinic action of alcuronium in conjunction with N-methylscopolamine is based on a shift by alcuronium of the interplay between agonist and antagonist in favour of the antagonist.