Bisquaternary Pyridinium Oximes as Presynaptic Agonists and Postsynaptic Antagonists of Muscarinic Receptors

Abstract: A study of the effects of bisquaternary pyridinium oximes on calcium‐dependent potassium‐evoked [³H]acetylcholine release from rat brain slices revealed that at presynaptic autoreceptors these drugs function like muscarinic agonists, as they mimic the effects of acetylcholine in their inhibition of the evoked [³H]‐acetylcholine release in an atropine‐sensitive and dose‐dependent manner. Since the bisquaternary pyridinium oximes are mild muscarinic antagonists at postsynaptic muscarinic receptors, they constitute a category of muscarinic ligands that are characterized by inverse dual activity at pre‐ and postsynaptic muscarinic receptors. These drugs may have dual function on cholinergic transmission by acting as presynaptic agonists and as postsynaptic antagonists. The most potent inhibitor of the evoked [³H]acetylcholine release was 1, 1′‐(4‐hydroxy‐iminopyridinium)trimethylene (TMB‐4) (I₅₀= 8 μM) and the weakest were 1‐(2‐hydroxyiminoethylpyridinium) 1‐(3‐cyclohexylcarboxypyridinium) dimethylether (HGG‐42) and 1‐(2‐hydroxyiminoethylpyridinium) 1‐(3‐phenyl‐carboxypyridinium) dimethylether (HGG‐12) (I₅₀= 150 μM). As postsynaptic antagonists, the latter drugs are more potent (K₁= 1.3‐3.3 μM) than TMB‐4 (K₁= 50 μM). Combined therapy with two drugs such as TMB‐4 and HGG‐12 might be effective in blocking severe hyper‐activity of the cholinergic system.