CHARACTERIZATION OF A NOVEL MUSCARINIC RECEPTOR AGONIST, YM796 - COMPARISON WITH CHOLINESTERASE-INHIBITORS IN IN-VIVO PHARMACOLOGICAL STUDIES

Previous reports have shown that (+/-)-YM796 (2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane) exhibits M(1) agonistic activity and ameliorates cognitive impairment, and that the (-)-S isomer is active in in vitro studies. We report here the characterization of the (-)-S isomer, YM796 ((-)-(S)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane L-tartrate monohydrate), and its (+)-R isomer in in vivo pharmacological studies in comparison with the cholinesterase inhibitors tacrine, amiridine and E-2020. YM796 (0.031-0.5 mg/kg p.o.), like the racemate, reversed the cognitive impairment in passive avoidance tasks of rats with nucleus basalis magnocellularis lesions, whereas (+)-R-YM796 was ineffective in this experimental amnesia. YM796 exhibited only weak effects on mouse salivation and hypothermia, a peripheral cholinergic response and a central cholinergic response, respectively. The (+)-R isomer, however, failed to induce these cholinergic responses. YM796 also ameliorated the memory deficits induced by scopolamine in rats and electroconvulsive shock in mice. The potency of YM796 in these experimental amnesia models was over a 100 times greater than that of tacrine, over 10 times greater than that of E-2020, and 6 times greater than that of amiridine. In salivary secretion and hypothermia, YM796 was 2-4 times weaker than tacrine and E-2020, and 1-2 times stronger than amiridine. Thus, YM796's ratio of anti-amnesic effects to salivary secretion and hypothermia was much greater than that of the cholinesterase inhibitors tested. Taken together with previous data which show that YM796, but not its(+)-R isomer, possesses M(1) agonistic activity, the difference between YM796 and the (+)-R isomer in anti-amnesic effects suggests that YM796 ameliorates cognitive impairment through, at least in part, the activation of central muscarinic M(1) receptors. Moreover, the fact that YM796 is more selective for anti-amnesic effects than other cholinergic responses may be due to its selectivity and efficacy for specific muscarinic receptor subtypes, predominantly for the M(1) subtype.