Roger Brodin

SR 46559 A and related aminopyridazines are potent muscarinic agonists with no cholinergic syndrome

The development of an aminopyridazine lead structure (minaprine) yielded compound SR 46559 A 3-[N-(2-diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, a novel and potent muscarinic agonist with no cholinergic syndrome.

SR 46559A: a novel and potent muscarinic compound with no cholinergic syndrome

The cholinergic activities of SR 46559A, 3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki=112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6–7 times lower. SR 46559A did not interact with brain nicotinic receptors and high affinity choline uptake sites nor did it inhibit brain acetylcholinesterase activity. In contrast to reference muscarinic agonists, SR 46559A (1 mM) did not inhibit the forskolin-induced activation of cAMP synthesis nor did it stimulate phosphoinositides breakdown in various brain preparations. However, this compound enhanced (+67% at 1 mM) diacylglycerol formation in rat striatal miniprisms, an effect fully reversed by atropine. As shown with reference agonists, SR 46559A inhibited (IC50=10 µM) the K+-evoked release of [3H]GABA from rat striatal slices and reduced at 0.5 and 1 µM, the population spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffers collateral commissural pathway in rat hippocampal slices. In mice, SR 46559A at a near lethal dose (200 mg/kg PO) did not induce the typical cholinergic syndrome nor did it modify at 30 mg/kg PO the oxotremorine-induced hypothermia. Like muscarinic agonists, SR 46559A (1 mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50=0.12 mg/kg PO) rotations induced in mice by intrastriatal injection of pirenzepine. SR 46559A prevented the scopolamine- or pirenzepine-induced deficit in passive avoidance learning, this compound being 3 times more potent on pirenzepine-induced amnesia. Moreover, using the social memory test, SR 46559A (0.1–3 mg/kg PO) enhanced short-term retention in adult rats and improved memory deficits observed in aged mice and in rats subjected to cerebral ischeamic insult. SR 46559A (1–3 mg/kg PO) also reversed the ischaemia-induced alterations of rats exploratory behaviour. Taken together, these results suggest that SR 46559A behaves as an atypical muscarinic compound which, at least in part, could stimulate muscarinic receptors coupled to phosphatidylcholine/phospholipases C or D signalling pathways. This drug has a marked ability to improve experimentally induced cognitive deficits in rodents without producing cholinergic symptomatology. Thus, SR 46559A could be a potential useful drug for the symptomatic treatment of Alzheimers disease.