Graham J. Durant

Asymmetric synthesis of a neuroprotective and orally active N-methyl-d-aspartate receptor ion-channel blocker, CNS 5788

Abstract Asymmetric synthesis of N -(2-chloro-5-methylthiophenyl)- N′ -(3-methylsulfinylphenyl)- N′ -methylguanidine (CNS 5788) was achieved in high enantiomeric excess through condensation of the cyanamide derivative, 6 and the sulfinylaniline hydrochloride, 5 . The key step involved the asymmetric oxidation of N -methyl-3-methylthioaniline using a Davis reagent.

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 Alzheimers 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.

A Convenient One Pot Procedure for N-Methylation of Aromatic Amines Using Trimethyl Orthoformate

Abstract Aromatic amines react with trimethyl orthoformate in the presence of concentrated sulfuric acid followed by acid hydrolysis to afford mono methylated amines in moderate to good yields.

Synthesis, biochemical activity and behavioral effects of a series of 1,4,5,6-tetrahydropyrimidines as novel ligands for M1 receptors

Abstract A series of novel tetrahydropyrimidines was synthesized and examined for M 1 muscarinic receptor activity. 1,4,5,6-Tetrahydro-5-methoxycarbonyl-pyrimidine hydrobromide ( 1a ; CDD-0034-C) displayed a high affinity for muscarinic receptors in rat brain and stimulated PI metabolism in rat hippocampus. Compound 1a ameliorated memory deficits associated with lesions of the septohippocampal cholinergic system in rats.