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

Abstract

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.

Pharmacological significance of triazole scaffold

“…The GH releasing mechanism was found to be mediated through a G-protein coupled receptor named growth hormone secretagogue receptor type 1 a (GHS-R1a) [73]. Presence of 1,2,4-triazole moiety was found in a series of potent agonist or antagonist G-protein coupled receptor ligands [74][75][76][77].…”

Synthesis and anti‐HIV activity of substituted 1,2,4‐triazolo‐thiophene derivatives

“…Recently, the short-lived reactive intermediates 1-(chloroalkyl)-1-aza-2-azoniaallene salts (4) were used by Jochims and coworkers [13] in the syn- thesis of various 1,2,4-triazole compounds via cycloaddition with various unsaturated precursors in the presence of SbCl 5 . In our recent work, these cations have been utilized in the synthesis of new types of 1,2,4-triazoles such as C-nucleosides [14,15], acyclic C-nucleosides [16], pyrimidines [17], N-alkylphthalimides [18], D-mannopentitol-1-yl-1,2,4-triazoles [19], 1H-indoles [20], quinolones [20], benzotriazoles [21], 3 -triazolo-thymidines [22], acetic acid alkylidene hydrazides [23], and 1,4-disubstituted piperazines [24,25].…”

“…• C. [1,2,4]triazolo [1,5-a] From 3b (1.20 g) [4][5]6,7, [1,2,4]triazolo [1,5-a]pyridine-2-yl)methyl)thiophene-2-yl)(4-nitro-phenyl)methanone (12). From 3c (1.17 g) and the nitrile 11 (1.36 …”

“…The 1,2,4-triazole moiety is present, for example, in certain antiasthmatic [1], antiviral (ribavirin) [2], antifungal (fluconazole) [3], antibacterial [4], and hypnotic [5] (triazolam) drugs. Owing to its broad spectrum of biological activity [6][7][8][9][10][11][12], the 1,2,4-triazole ring system represents an attractive target for the elaboration of solid-phase synthesis and the production of combinatorial libraries.…”

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“…Over the past few decades, the biological and pharmaceutical applications of 1, 2, 4-triazoles have fashioned substantial interest in their synthesis and characterization. 1, 2, 4-triazoles and their derivatives possess differing activities which range from antiasthmatic 21 , antiviral (ribavirin) 22 , antifungal (fluconazole) 23 , antibacterial 24 , hypnotics 25 (triazolam) to anticancer. In this regard, we come up with the hypothesis that incorporation of 1H-1, 2, 4-triazole into the multi-substituted 2-amino thiophene unit may enhance their biological activity.…”