POSITIVE AND NEGATIVE ALLOSTERIC INTERACTIONS ON MUSCARINIC RECEPTORS

It was previously found that alcuronium increases the binding of [H-3] methyl-N-scopolamine to cardiac muscarinic receptors by a positive all osteric action while its effect on the binding of [H-3]quinuclildinyl benzilate is negative. The features of the antagonist's molecule which decide whether its allosteric interaction with alcuronium is positive or negative are not known. In the present work, it was found that alc uronium has a positive allosteric effect also on the binding of [H-3]a tropine and [H-3]methyl-N-piperidinyl benzilate to muscarinic receptor s in rat heart atria and that its effect on the binding of [H-3]methyl -N-quinuclidinyl benzilate is negative. A comparison of the five radio labelled antagonists that have been investigated so far indicates that the type of allosteric interaction (positive or negative) is not dete rmined by the presence or absence of the quaternary nitrogen or of the benzilyl moiety in the molecule of the antagonist. Apparently, featur es of the N-bearing moiety of muscarinic antagonists other than the pr esence of a charge an nitrogen play a key role in the determination of the type of interaction.