title: Functionally selective M1 muscarinic agonists. 3. Side chains and azacycles contributing to functional muscarinic selectivity among pyrazinylazacycles.
abstract: In an attempt to improve upon the M1 agonist activity of the selective M1 agonist xanomeline and related compounds, the M1 muscarinic efficacies and potencies of 3- and 6-substituted pyrazinylazacycles were varied by changing both the 3- and 6-substituents as well as the azacycle. Significant improvements in efficacy and potency over the previously prepared [3-(hexyloxy)pyrazinyl]tetrahydropyridine 19 were obtained with the [3-(hexyloxy)pyrazinyl]-quinuclidine 5i. The M1 activity of 5i showed some enantioselectivity with (S)-5i being ca. 4-fold more potent than (R)-5i. Like 19 and xanomeline, 5i was a functionally selective M1 agonist that showed greater functional selectivity than widely studied pyrazinylquinuclidine 5n (L-689,660). The improved functional selectivity of 5i over 5n could be attributed to the additional binding interactions between the hexyloxy side chain of 5i and the M1 receptor that are not available to 5n. Although 5i may show M1 functional selectivity comparable to xanomeliine, 5i is a less efficacious and potent M1 agonist than xanomeline.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: L
authors.initials: L
authors.lastname: Merritt
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: B D
authors.initials: BD
authors.lastname: Sawyer
authors.forename: C H
authors.initials: CH
authors.lastname: Mitch
authors.forename: J B
authors.initials: JB
authors.lastname: Deeter
authors.forename: S C
authors.initials: SC
authors.lastname: Peters
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: P H
authors.initials: PH
authors.lastname: Olesen
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002460:Cell Line; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018721:Muscarinic Agonists; D011719:Pyrazines; D011725:Pyridines; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; C076265:L 689660; C075257:xanomeline