Synthesis and Antimuscarinic Properties of Quinuclidin-3-yl 1,2,3,4-Tetrahydroisoquinoline-2-carboxylate Derivatives as Novel Muscarinic Receptor Antagonists

In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth

The Berkman Syme social network index.

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Forest plots and pooled estimates hazard ratios of social isolation for all-cause mortality are shown separately for different social isolation assessment tools.

The hazard ratio among the studies using the Berkman-Syme Social Network Index to assess social isolation is 1.35 (95% CI; 1.24–1.47) with substantial heterogeneity (heterogeneity: Chi² = 39.10, P < 0.0001, I² = 74%) whereas that among the remainders is 1.33 (95% CI; 1.23–1.44) with substantial heterogeneity (heterogeneity: Chi² = 60.22, P < 0.00001, I² = 73%).</p

Forest plots and pooled estimates hazard ratios of social isolation for all-cause mortality are shown separately for different regions in the world.

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Results of risk of bias across the studies.

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Forest plots and pooled estimates for hazard ratios of social isolation for all-cause mortality.

The random effects weighted average hazard ratios of social isolation for all-cause mortality is 1.33 (95% CI); 1.26–1.41) with substantial heterogeneity (heterogeneity: Chi² = 112.51, P < 0.00001, I² = 76%).</p

PRISMA flow diagram.

A total of 36 studies were identified for inclusion in the reviews, after a two-stage screening process. Twenty-seven studies among them were included in meta-analyses.</p

PRISMA checklist.

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Forest plots and pooled estimates hazard ratios of social isolation for all-cause mortality are shown separately for different country income levels.

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Characteristics of 36 studies included in this systematic review.

Characteristics of 36 studies included in this systematic review.</p