Synthesis and muscarinic activity of quinuclidinyl- and (1- azanorbornyl)pyrazine derivatives
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.
Synthesis of Azabicyclic Pyrazine Derivatives as Muscarinic Agonists and the Preparation of a Chloropyrazine Analogue with Functional Selectivity at Sub-types of the Muscarinic Receptor
The synthesis of quinuclidine and azanorbornyl pyrazine derivatives has yielded highly potent and efficacious muscarinic agonists; chloro-substitution in the pyrazine ring of the quinuclidine analogue resulted in the formation of a derivative with both enantiomers displaying partial agonist character but, more importantly, functional selectivity at the M1, M2 and M3 sub-types of the muscarinic receptor.
Baker, Raymond,Street, Leslie J.,Reeve, Austin J.,Saunders, John
p. 760 - 762
(2007/10/02)
More Articles about upstream products of 135276-26-5