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Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists.

Abstract：

: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. 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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Ojo B,Dunbar PG,Durant GJ,Nagy PI,Huzl JJ 3rd,Periyasamy S,Ngur DO,el-Assadi AA,Hoss WP,Messer WS Jr

doi

10.1016/0968-0896(96)00152-6

subject

Has Abstract

pub_date

1996-10-01 00:00:00

pages

1605-15

issue

10

eissn

0968-0896

issn

1464-3391

pii

0968089696001526

journal_volume

4

pub_type

杂志文章

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