Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M sub(1) muscarinic receptor agonists

A series of 5-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines was synthesized for biological evaluation as selective agonists for M sub(1) receptors coupled to phosphoinositide (PI) metabolism in the central nervous system. Each ligand bound with high affinity to muscarinic receptors from rat brain as measured by inhibition of [ super(3)H]-(R)-quinuclidinyl benzilate ([ super(3)H]-(R)-QNB) binding. 5-(3-Methyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine trifluoroacetate (CDD-0098-J) displayed high affinity (IC sub(50) = 2.7 plus or minus 0.69 mu M) and efficacy at muscarinic receptors coupled to PI metabolism in the rat cortex and hippocampus. Increasing the length of the alkyl substituent increased affinity for muscarinic receptors yet decreased activity in PI turnover assays.