Synthesis and muscarinic activity of quinuclidinyl- and (1-azanorbornyl)pyrazine derivatives

• Published in: Journal of medicinal chemistry Vol. 35; no. 2; pp. 295 - 305
• Main Authors: Street, Leslie J, Baker, Raymond, Book, Tracey, Reeve, Austin J, Saunders, John, Willson, Timothy, Marwood, Rosemarie S, Patel, Shailendra, Freedman, Stephen B
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.01.1992
• Subjects: Animals; Binding, Competitive; Cerebral Cortex - metabolism; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; In Vitro Techniques; Norbornanes - chemical synthesis; Norbornanes - metabolism; Organic chemistry; Parasympathomimetics - chemical synthesis; Parasympathomimetics - metabolism; Preparations and properties; Pyrazines - chemical synthesis; Pyrazines - metabolism; Quinuclidines - chemical synthesis; Quinuclidines - metabolism; Rats; Receptors, Muscarinic - metabolism; Structure-Activity Relationship; Stereoisomer; Agonist; Angular nitrogen heterocycle; Nitrogen heterocycle; Six membered ring; Bicyclic compound; Muscarinic receptor; In vitro; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00080a014

The synthesis and cortical muscarinic activity of a novel series of pyrazine-based agonists is described. Quinuclidine and azanorbornane derivatives were prepared either by reaction of lithiated pyrazines with azabicyclic ketones, followed by chlorination and reduction, or by reaction of the lithium enolate of the azabicyclic ester with 2-chloropyrazines followed by ester hydrolysis and decarboxylation. Substitution at all three positions of the heteroaromatic ring has been explored. Optimal muscarinic agonist activity was observed for unsubstituted pyrazines in the azanorbornane series. The exo-1-azanorbornane 18a is one of the most efficacious and potent centrally active muscarinic agonists known. Studies on the 3-substituted derivatives have provided evidence of the preferred conformation of these ligands for optimal muscarinic activity. Substitution at C6 gave ligands with increased affinity and reduced efficacy. Moving the position of the diazine ring nitrogens to give pyrimidine and pyridazine derivatives resulted in a significant loss of muscarinic activity.