Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands

• Published in: Journal of medicinal chemistry Vol. 35; no. 13; pp. 2392 - 2406
• Main Authors: Jenkins, Sarah M, Wadsworth, Harry J, Bromidge, Steven, Orlek, Barry S, Wyman, Paul A, Riley, Graham J, Hawkins, Julie
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.06.1992
• Subjects: Alzheimer Disease - drug therapy; Animals; 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; Ligands; Organic chemistry; Preparations and properties; Radioligand Assay; Rats; Receptors, Muscarinic - metabolism; Substrate Specificity; Tetrazoles - metabolism; Tetrazoles - therapeutic use; Triazoles - metabolism; Triazoles - therapeutic use; Substituent effect; Five membered ring; Angular nitrogen heterocycle; Nitrogen heterocycle; Bicyclic compound; Muscarinic receptor; In vitro; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00091a007

The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands has been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.