ANTIMUSCARINIC 3-(2-FURANYL)QUINUCLIDIN-2-ENE DERIVATIVES - SYNTHESISAND STRUCTURE-ACTIVITY-RELATIONSHIPS

A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)q uinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs usi ng (-)-[H-3]-3-quinuclidinyl benzilate as the radioligand, and the ant imuscarinic potency was determined in a functional assay on isolated g uinea pig urinary bladder using carbachol as the agonist. Several of t he novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is mode rate (K-i 300 nM), it is much higher for the 6-methyl (49; K-i = 12 nM ), 5-ethyl (52; K-i = 7.4 nM), 5-bromo (33; K-i = 6.4 nM), and 3-pheny l (49; K-i = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phen yl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slight ly increases affinity (K-i = 1.55 and 2.39 nM, respectively). The conf ormational preferences of the 3-phenyl (49) and 5-phenyl (51) derivati ves were studied by X-ray crystallography and molecular mechanics calc ulations. Because of the observed high affinity of 49, a series of 16 meta-and para-substituted analogues of 49 was synthesized and tested. derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new serie s are well described with QSAR and CoMFA models.