| Abstract
| - A series of 25 derivatives of the muscarinic antagonist3-(2-furanyl)quinuclidin-2-ene (4) wassynthesized and evaluated for muscarinic and antimuscarinic properties.Substitution at allthree positions of the furan ring has been investigated. Theaffinities of the new compoundswere determined by competition experiments in homogenates of cerebralcortex, heart, parotidgland, and urinary bladder from guinea pigs using(−)-[3H]-3-quinuclidinyl benzilate as theradioligand, and the antimuscarinic potency was determined in afunctional assay on isolatedguinea pig urinary bladder using carbachol as the agonist. Severalof the novel derivativesdisplayed high muscarinic affinities. Whereas the affinity of leadcompound 4 for corticalmuscarinic receptors is moderate (Ki = 300nM), it is much higher for the 5-methyl (48;Ki =12 nM), 5-ethyl (52; Ki = 7.4 nM),5-bromo (33; Ki = 6.4 nM), and3-phenyl (49; Ki = 2.8nM)substituted derivatives. The substituent-induced increases inaffinity do not appear to beadditive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl(55) substitution pattern onlyslightly increases affinity (Ki = 1.55 and2.39 nM, respectively). The conformationalpreferencesof the 3-phenyl (49) and 5-phenyl (51)derivatives were studied by X-ray crystallography andmolecular mechanics calculations. Because of the observed highaffinity of 49, a series of 16meta- and para-substituted analogues of 49 was synthesizedand tested. The m-hydroxyderivative (68) exhibited more than 10-fold improvement inaffinity as compared to 49. Thestructure−activity relationships of the new series are well describedwith QSAR and CoMFAmodels.
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