Competitive interaction of gallamine with multiple muscarinic receptors

Gallamine, a cholinergic antagonist at the (nicotinic) neuromuscular junction, possesses antimuscarinic potency in several systems. We report here that gallamine inhibited the binding of [³H]quinuclidinyl benzilate (QNB) in a competitive manner in the brainstem and forebrain of the rat. The occupancy curves derived from these studies suggest that gallamine has widely varying affinities for different subpopulations of muscarinic receptors, a finding which sets gallamine apart from classical muscarinic antagonists such as atropine and QNB. The greatest difference in affinities for gallamine occurred in the brainstem, where the data could be satisfactorily fitted to a two-site model, with 77% of the receptors having high affinity (K_d = 25 nM) and 23% low affinity (93 μM). Further, these affinities displayed rank order correlation with those of carbachol (an agonist), although gallamine has not, so far, displayed agonist (or partial agonist) activity. The finding that antagonists as well as agonists can display multiple affinities for muscarinic receptors suggests that there are fundamental differences among subpopulations of these receptors.