Tetrahydropyrimidine derivatives display functional selectivity for M1 muscarinic receptors in brain

Selective muscarinic agonists might be useful in the treatment of Alzheimer's disease. Previous studies identified several amidine derivatives as selective and efficacious m1 agonists, using muscarinic receptor subtypes expressed in cell lines. In the present studies, the functional selectivities, side effect profiles and memory-enhancing properties of these ligands were examined through a series of in vitro and in vivo experiments. CDD-0078, CDD-0097, and CDD-0102 behaved as partial agonists by stimulating PI turnover in rat cortical slices to roughly 100% above basal levels. Pirenzepine was more potent than either AF-DX 116 or p-F-hexahydrosiladifenidol (p-F-HHSiD) in blocking the PI responses of each ligand, suggesting that the responses were due to activation of M1 receptors. The time course of pharmacological responses was examined following i.p. injections of muscarinic agonists. Low does (0.1 and 1.0 mg/kg) of CDD-0078, CDD-0097, and CDD-0102 did not elicit signs of cholinergic activity during the 2-hr testing period. The highest dose tested (10 mg/kg) produced a modest degree of salivation and lacrimation during the first 30-min period. Core body temperature remained unaffected. Central nervous system (CNS) penetration was evaluated through ex vivo binding studies. CDD-0097 inhibited 1.0 nM [3H]pirenzepine binding in a dose-dependent manner 30 min following i.p. injections. In behavioral studies, CDD-0097 (1.0 mg/kg) completely reversed the memory deficits induced by hemicholinium-3 or by IgG-192 saporin in two types of memory tasks. It did not impair the performance of control animals in either task. In summary, CDD-0097 displayed a limited side-effect profile and the ability to penetrate into the central nervous system and stimulate M1 receptors. The amidine derivatives should be useful in further exploring the functional consequences of activating M1 muscarinic receptors in the CNS. The beneficial effects of CDD-0097 on memory function warrant further examination of the compound as a selective M1 agonist for the treatment of Alzheimer's disease. Drug Dev. Res. 40:171–184, 1997. © 1997 Wiley-Liss, Inc.