SR-46559A - A NOVEL AND POTENT MUSCARINIC COMPOUND WITH NO CHOLINERGIC SYNDROME

The cholinergic activities of SR 46559A, 3- [N-(2 diethyl-amino-2-meth ylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortica l membranes, SR 46559A was a competitive ligand (K(i) = 112 nM) at mus carinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6-7 times lower. SR 46559A did not interac t with brain nicotinic receptors and high affinity choline uptake site s 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 p hosphoinositides breakdown in various brain preparations. However, thi s compound enhanced ( + 67% at 1 mM) diacylglycerol formation in rat s triatal miniprisms, an effect fully reversed by atropine. As shown wit h reference agonists, SR 46559A inhibited (IC50 = 10 muM) the K+-evoke d release of [H-3]GABA from rat striatal slices and reduced at 0.5 and 1 muM, the population spike amplitude of the CA1 pyramidal cells indu ced by stimulation of the Schaffer's 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 musca rinic agonists, SR 46559A (I mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50 = 0.12 mg/kg PO) rotations indu ced in mice by intrastriatal injection of pirenzepine. SR 46559A preve nted the scopolamine- or pirenzepine-induced deficit in passive avoida nce learning, this compound being 3 times more potent on pirenzepine-i nduced 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 cerebra l ischeamic insult. SR 46559A (1-3 mg/kg PO) also reversed the ischaem ia-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 receptor s coupled to phosphatidylcholine/phospholipases C or D signalling path ways. This drug has a marked ability to improve experimentally induced cognitive deficits in rodents without producing cholinergic symptomat ology. Thus, SR 46559A could be a potential useful drug for the sympto matic treatment of Alzheimer's disease.