TETRAHYDROPYRIMIDINE DERIVATIVES DISPLAY FUNCTIONAL SELECTIVITY FOR M-1 MUSCARINIC RECEPTORS IN BRAIN

Selective muscarinic agonists might be useful in the treatment of Alzh eimer's disease. Previous studies identified several amidine derivativ es as selective and efficacious m1 agonists, using muscarinic receptor subtypes expressed in cell lines. In the present studies, the functio nal selectivities, side effect profiles and memory-enhancing propertie s of these ligands were examined through a series of in vitro and in v ivo experiments. CDD-0078, CDD-0097, and CDD-0102 behaved as partial a gonists by stimulating Pl turnover in rat cortical slices to roughly 1 00% above basal levels. Pirenzepine was more potent than either AF-DX 116 or p-F-hexahydrosiladifenidol (p-F-HHSiD) in blocking the Pl respo nses of each ligand, suggesting that the responses were due to activat ion of M-1 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 high est dose tested (10 mg/kg) produced a modest degree of salivation and lacrimation during the first 30-min period. Core body temperature rema ined unaffected. Central nervous system (CNS) penetration was evaluate d through ex vivo binding studies. CDD-0097 inhibited 1.0 nM [H-3]pire nzepine binding in a dose-dependent manner 30 min following i.p. injec tions. In behavioral studies, CDD-0097 (1.0 mg/kg) completely reversed the memory deficits induced by hemicholinium-3 or by lgG-192 saporin in two types of memory tasks. It did not impair the performance of con trol animals in either task. In summary, CDD-0097 displayed a limited side-effect profile and the ability to penetrate into the central nerv ous system and stimulate M-1 receptors. The amidine derivatives should be useful in further exploring the functional consequences of activat ing M-1 muscarinic receptors in the CNS. The beneficial effects of CDD -0097 on memory function warrant further examination of the compound a s a selective M-1 agonist for the treatment of Alzheimer's disease. (C ) 1997 Wiley-Liss, Inc.