Comparison of azabicyclic esters and oxadiazoles as ligands for the muscarinic receptor

Abstract

The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents. This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor. Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system. These compounds generally show improved affinity relative to the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine. Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.

Preparation of novel azabicyclic amines and α7 nicotinic acetylcholine receptor activity of derived aryl amides

“…Also, a report from the muscarinic literature suggested that 1-azabicyclo-[3.2.1]octane can function as an effective isostere of quinuclidine [9]. Chlorobenzamide (±)-1 was initially prepared in racemic form (Scheme 1).…”

1,2,4-oxadiazole: A Brief Review from the Literature About the Synthesis and Pharmacological Applications

“…The synthesis and the evaluation of several derivatives of the group in question, where the affinity by muscarinic receptors is strong, puts them among the possible drugs for the treatment of Alzheimer´s disease (ORLEK et al, 1991).…”

Synthesis, characterization, and antimicrobial activities of clubbed [1,2,4]‐oxadiazoles with fluorobenzimidazoles

“…The oxadiazole moiety is an important structure unit in drugs and chemical materials [12]. Among these oxadiazoles, [1,2,4]-oxadiazoles are gaining interest in the medicinal chemistry [13] and shows numerous biological activities including muscarinic agonists [14], dopamine transporters [15], benzodiazepine receptor partial agonists [16], nematocidal, fungicidal, and microbicides [17], immunosuppressants [18], Fab I inhibitors as antibacterial agents [19], antiplatelet and antithrombotic agents [20], etc. Also, oxadiazoles plays an important role as bioisosteres for amides and esters [21].…”