Functionally selective M1 muscarinic agonists. 3. Side chains and azacycles contributing to functional muscarinic selectivity among pyrazinylazacycles
| Autor: | Jack B. Deeter, David O. Calligaro, Per Sauerberg, Harlan E. Shannon, Leander Merritt, Franklin Porter Bymaster, Steven C. Peters, John S. Ward, Swedberg, B.D. Sawyer, Malcolm J. Sheardown, Charles H. Mitch, Preben H. Olesen |
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| Rok vydání: | 1995 |
| Předmět: |
Agonist
Male Stereochemistry medicine.drug_class Pyridines Pharmacology Muscarinic Agonists Cell Line Rats Sprague-Dawley chemistry.chemical_compound Bridged Bicyclo Compounds Mice Structure-Activity Relationship Thiadiazoles Drug Discovery Muscarinic acetylcholine receptor Functional selectivity medicine Structure–activity relationship Animals Chemistry Muscarinic acetylcholine receptor M1 Bridged Bicyclo Compounds Heterocyclic Receptors Muscarinic Rats Pyrazines Molecular Medicine Xanomeline Selectivity |
| Zdroj: | Journal of medicinal chemistry. 38(18) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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