247079-84-1Relevant articles and documents
Structural Features of Iperoxo–BQCA Muscarinic Acetylcholine Receptor Hybrid Ligands Determining Subtype Selectivity and Efficacy
Capuano, Ben,Chalmers, David K.,Christopoulos, Arthur,Davie, Briana J.,Scammells, Peter J.,Valant, Celine,Wakeham, Matthew C. L.
, p. 97 - 111 (2021/12/27)
Selective agonists for the human M1 and M4 muscarinic acetylcholine receptors (mAChRs) are attractive candidates for the treatment of cognitive disorders, such as Alzheimer’s disease and schizophrenia. Past efforts to optimize a ligand for selective agonism at any one of the M1–M5 mAChR subtypes has proven to be a significant challenge. Recently, research efforts have demonstrated that hybrid ligands may offer a potential solution to the lack of selectivity at mAChRs. In an attempt to design M1 mAChR selective agonists by hybridizing an M1 mAChR selective positive allosteric modulator [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] and a potent agonist [(4-[(4,5-dihydro-3-isoxazolyl)oxy]-N,N,N-trimethyl-2-butyn-1-aminium iodide) (iperoxo)], we unexpectedly discovered that these ligands possessed noticeable M2/M4 mAChR selectivity. Evaluation of truncated derivatives of the hybrid ligands at the M1–M5 mAChR subtypes suggests that the allosteric pharmacophore of iperoxo-based mAChR hybrid ligands likely sterically disrupts the allosteric site of the mAChRs, attenuating the efficacy of M1/M3/M5 mAChR responses compared to M2/M4 mAChRs, resulting in a preference for the M2/M4 mAChRs. However, at certain intermediate linker lengths, the effects of this apparent disruption of the allosteric site are diminished, restoring nonselective agonism and suggesting a possible allosteric interaction which is favorable to efficacy at all M1–M5 mAChRs.
Convergent, short synthesis of the muscarinic superagonist iperoxo
Kloeckner, Jessica,Schmitz, Jens,Holzgrabe, Ulrike
experimental part, p. 3470 - 3472 (2010/08/20)
Up to now the availability of iperoxo, an important superagonist of the muscarinic acetylcholine receptors, was limited because the synthesis of its precursor, the iperoxo base, was characterized by low yields, laborious chromatography and low reproducibility. Here we report a robust convergent three-step synthesis by means of a Mannich reaction and nucleophilic substitution at the 3-nitro-Δ2-isoxazoline. The new route combines short reaction time, high reproducibility and an overall yield increased from 12% to 42%.
Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M
Dallanoce, Clelia,Conti, Paola,De Amici, Marco,De Micheli, Carlo,Barocelli, Elisabetta,Chiavarini, Milena,Ballabeni, Vigilio,Bertoni, Simona,Impicciatore, Mariannina
, p. 1539 - 1547 (2007/10/03)
Two subseries of nonquaternized (5a-10a) and quaternized derivatives (5b-10b) related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compounds was estimated in three class
Synthesis and binding affinity of new muscarinic ligands structurally related to oxotremorine
Conti, Paola,Dallanoce, Clelia,De Amici, Marco,De Micheli, Carlo,Ebert, Bjarke
, p. 1033 - 1036 (2007/10/03)
The synthesis and radioligand binding assays of a group of muscarinic ligands related to oxotremorine are reported. The new compounds displayed binding affinities comparable to those of the parent molecule with the exception of the trimethylammonium salt
