FUNCTIONALLY SELECTIVE M(1) MUSCARINIC AGONISTS .3. SIDE-CHAINS AND AZACYCLES CONTRIBUTING TO FUNCTIONAL MUSCARINIC SELECTIVITY AMONG PYRAZINYLAZACYCLES

In an attempt to improve upon the M(1) agonist activity of the selecti ve M(1) agonist xanomeline and related compounds, the M(1) muscarinic efficacies and potencies of 3- and 6-substituted pyrazinylazacycles we re varied by changing both the 3- and 6-substituents as well as the az acycle. Significant improvements in efficacy and potency over the prev iously prepared [3-(hexyloxy)pyrazinyl]tetrahydropyridine 19 were obta ined with the [3-(hexyloxy)pyrazinyl]quinuclidine 5i. The M(1) activit y of 5i showed some enantioselectivity with (S)-5i being ca. 4-fold mo re potent than (R)-5i. Like 19 and xanomeline, 5i was a functionally s elective M(1) agonist that showed greater functional selectivity than widely studied pyrazinylquinuclidine 5n (L-689,660). The improved func tional selectivity of 5i over 5n could be attributed to the additional binding interactions between the hexyloxy side chain of 5i and the M( 1) receptor that are not available to 5n. Although 5i may show M(1) fu nctional selectivity comparable to xanomeliine, 5i is a less efficacio us and potent M(1) agonist than xanomeline.