3-(2-Benzofuranyl)quinuclidin-2-ene Derivatives:  Novel Muscarinic Antagonists

Abstract

A series of 26 derivatives of the novel muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for muscarinic and antimuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic-potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure-activity relationship models were developed for this series of substituted benzofuranyl derivatives.

QMOD: physically meaningful QSAR

“…The second set, illustrated in Figure 4, consisted of all furan-based quinuclidinene muscarinic antagonists from two structure-activity studies, with the addition of two benzofuran compounds for testing non-additive predictions [20; 21]. The activity range was pK d 5.0–8.0.…”

“…The four muscarinic antagonists shown were synthesized as part of the same effort for developing a treatment for urinary incontinence [20; 21]. While two single changes from the parent compound yielded improvements over a full log unit in K d , the combination of the two changes was worse than either of the singly substituted compounds.…”

Receptor binding studies of soft anticholinergic agents

“…The pK i (m 3 ) were correlated in decreasing order with ovality (O e , r = 0.65), dipole moment ( D, r = 0.53), and calculated lipophilicity (QLogP, r = 0.39). Lipophilicity has been long recognized as an important factor determining antimuscarinic activity (54)(55)(56). Because O e and D are essentially perpendicular (show very little intercorrelation: r = -0.038, Table 9) and both of them are well correlated with pK i (m 3 ), the combination gives a reasonably good description: pK i (m 3 Table 8) provides some improvement in the correlation (r = 0.88, SE = 0.39) and is statistically justified (at a p < 0.06 level), but because on the included data O e and QLogP are intercorrelated, the improvement is less significant.…”

Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose

“…The muscarinic set is analyzed in much more detail here than in prior work with QMOD [ 24 ]. The numbering scheme for the muscarinic antagonists used here was taken from the original reports, with series A numbering from Johansson et al [ 42 ] and series B from Nordvall et al [ 43 ].…”