Aminopyridazines--an alternative route to potent muscarinic agonists with no cholinergic syndrome.
In the search for central cholinergic agents which do not derive from already well-known agonists such as arecoline, pilocarpine or oxotremorine, we selected minaprine [3-(beta-morpholinoethylamino)-4-methyl-6-phenyl-pyridazine dihydrochloride] as a lead structure. Effectively, beside its antidepressive properties, minaprine shows a weak but highly selective affinity for hippocampic M1 receptors (IC50 = 17.10(-6) [3H]-pirenzepine). On the other hand minaprine has an excellent bioavailability and is well tolerated in human; particularly, minaprine does not induce any cholinergic syndrome. The synthesis of about 300 minaprine analogues was then undertaken using information resulting from a computer graphics analysis of published muscarinic ligands as well as classical structure-activity relationship considerations. These studies identified the features which are associated with high affinity for the muscarinic M1 receptors and led to the synthesis of ligands 5660 times more potent than minaprine. Taking into account factors such as the absence of a chiral center, the duration of activity, the metabolic stability led us to select compound SR 46559 A [3-(N-(2-diethylamino-2-methylpropyl)-6-phenyl-5-propylpyridazinamine sesquifumarate] for the industrial development. This compound is a potent orally active muscarinic agent, with no cholinergic symptom.
Laboratoire de Pharmacochimie Moléculaire, Université Louis Pasteur Strasbourg, France.
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Wermuth
D000818:Animals; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010277:Parasympathomimetics; D011724:Pyridazines