Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists

As part of a continuing effort aimed at the development of selective, efficacious, and centrally active m1 muscarinic agonists for the treatment of Alzheimer's disease, a series of amide and hydrazide amidine derivatives ( 2a–e and 3b–d) was synthesized and examined for muscarinic agonist activity. Preliminary biochemical studies indicated that 2b, 2d, and 3d bound to muscarinic receptors in rat brain and stimulated phosphoinositide (PI) metabolism in rat cerebral cortex. Compounds 2b and 2d were also highly efficacious at m1 muscarinic receptors expressed in cultured A9 L cells. Molecular modeling studies suggest slightly different modes of interaction with m1 receptors for the ester and amide derivatives. Also, hydrogen-bond formation with a Thr residue may be important for m1 muscarinic agonist potency. The data suggest that the amide moiety can replace the ester group found in muscarinic agonists and provide further support for the utility of amidine derivatives in the development of efficacious m1 agonists. Several amidine derivatives (e.g. 1b and 1e) display selective m1 muscarinic agonist activity, and may be useful in the treatment of Alzheimer's disease. To further develop the amidine series, a number of amide and hydrazine derivatives ( 2a-e) and 3b-d) were synthesized and examined for m1 muscarinic agonist activity.