In vivo characterisation of novel efficacious muscarinic receptor agonists

Although a number of muscarinic agonists have been used in clinical trials for Alzheimer's Disease, many of these compounds are low in potency and have only limited intrinsic efficacy. The present study describes four non-quaternary oxadiazole based muscarinic agonists from a quinuclidine and a 1-azanorbornane series. These displayed up to 1000 fold higher affinity than arecoline and were efficacious muscarinic agonists at cortical receptors. All four compounds produced peripherally mediated salivation and centrally mediated hypothermia at doses 50-50,000 fold lower than arecoline. The most potent was L-670,548, the methyl oxadiazole in the 1-azanorbornane series, which had an ED50 of 0.0016 mg/kg on the hypothermia model. This derivative was also the most potent compound in ex vivo binding studies (ED50 0.0069 mg/kg) and showed excellent brain penetration (3.8% of the administered dose). These derivatives are the first non quaternary efficacious agonists which show good penetration into the CNS (central nervous system), and will prove useful tools in understanding the role of muscarinic receptors in CNS function.