title: 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.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Medicinal Research Centre, Harlow, Essex, U.K.
authors.forename: S M
authors.initials: SM
authors.lastname: Jenkins
authors.forename: H J
authors.initials: HJ
authors.lastname: Wadsworth
authors.forename: S
authors.initials: S
authors.lastname: Bromidge
authors.forename: B S
authors.initials: BS
authors.lastname: Orlek
authors.forename: P A
authors.initials: PA
authors.lastname: Wyman
authors.forename: G J
authors.initials: GJ
authors.lastname: Riley
authors.forename: J
authors.initials: J
authors.lastname: Hawkins
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D008024:Ligands; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013379:Substrate Specificity; D013777:Tetrazoles / Q000378:metabolism* / Q000627:therapeutic use; D014230:Triazoles / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D008024:Ligands; D011976:Receptors, Muscarinic; D013777:Tetrazoles; D014230:Triazoles