The processing of the selective M1 agonist CDD-0102-J by human hepatic drug metabolizing enzymes.

The in vitro metabolism of the selective M1 muscarinic agonist CDD-0102-J was evaluated in heterologous systems expressing individual human cytochrome P-450 (CYP) isoenzymes and also in suspensions of cryopreserved human hepatocytes. In all experiments, the metabolism of CDD-0102-J was characterized based on its rate of disappearance using an HPLC assay since no metabolites have as yet been characterized. The human CYP isoenzymes used were CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 3A4.

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.

1,2,5-Thiadiazole derivatives of arecoline stimulate M1 receptors coupled to phosphoinositide turnover.

A series of alkoxy-1,2,5-thiadiazole derivatives of arecoline was synthesized in an effort to develop M1 muscarinic agonists. The 3-butenyloxy, 2-butynyloxy, cyclopropylmethyloxy, and hexyloxy derivatives stimulated phosphoinositide turnover through muscarinic receptors in the rat hippocampus. The dose-response curves of 2-butynyloxy, cyclopropylmethyloxy and hexyloxy compound together was the same as the response of each separately.

Regulation of the phosphoinositide cascade by polyamines in brain.

The endogenous polyamines spermidine and spermine enhanced guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S)-stimulated phosphoinositide turnover with EC50 values of 100 +/- 30 and 50 +/- 15 microM, respectively, whereas the synthetic polyamines N,N'-bis(3-aminopropyl)-1,3-propanediamine and -ethylenediamine inhibited GTP-gamma-S-stimulated phosphoinositide turnover, with maximal inhibition at 1 mM. Kinetic analysis of GTP-gamma-S-stimulated phosphoinositide turnover in the absence and presence of spermidine showed that the Km for GTP-gamma-S was not changed (1,303 +/- 270 and 1,069 +/- 214 nM, respectively), whereas the Vmax was increased by 206% (1,566 +/- 141 and 4,792 +/- 84 cpm, respectively), indicating that spermidine and GTP-gamma-S acted at different sites. Spermidine also enhanced Ca(2+)-stimulated phosphoinositide turnover in the absence of GTP-gamma-S by decreasing the Ca2+ requirement of the phosphoinositide-specific phospholipase C.

Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists.

A series of 5-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines+ ++ (7a-h) was synthesized for biological evaluation as selective agonists for M1 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 [3H]-(R)-quinuclidinyl benzilate ([3H]-(R)-QNB) binding. 5-(3-Methyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine+ ++ trifluoroacetate (CDD-0098-J;7a) displayed high affinity (IC50 = 2.