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

Abstract

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.

Exploring the binding site of the human muscarinic M3 receptor: Homology modeling and docking study

“…1) and 17 selective hM3 antagonists (Table I) were chosen [17][18][19]. The 2D starting structure of each ligand was drawn with ISIS Draw [20], and was converted to the 3D structure with the ModelBuilder module from the HyperChem7.52 package.…”

Magnetic Combined Cross-Linked Enzyme Aggregates of Ketoreductase and Alcohol Dehydrogenase: An Efficient and Stable Biocatalyst for Asymmetric Synthesis of (R)-3-Quinuclidinol with Regeneration of Coenzymes In Situ

“…For instance, (R)-3-quinuclidinol is a key chiral intermediate of many drugs such as aclidinium bromide [4], solifenacin succinate [5] and revatropate [6]. Aclidinium and revatropate are anticholinergic for long-term management of chronic obstructive pulmonary disease (COPD) which leads to more than 3 million deaths worldwide every year [7] and is also the third leading cause of death in United States following cancer and heart disease.…”

Stereoselective Total Syntheses of Solifenacin and N-Acetyl-1-(4-chloro­phenyl)-6,7-dimethoxytetrahydroisoquinoline

“…1 In particular, (R)-3-quinuclidinyl ester of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid (1, solifenacin) is a competitive muscarinic acetylcholine receptor antagonist currently used in the treatment of overactive bladders. 2 On the other hand, N-acetyl-1- (4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2) is a potent 2-amino-3- (3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonist. 3 AMPA receptor antagonists are used as neuroprotective agents in the treatment of neurological diseases such as epilepsy, ischemia, Parkinson's disease, and multiple sclerosis.…”

“…9 The sulfinyl group is highly stereodirecting and activates the C=N bond effectively in nucleophilic addition reactions, and can easily be removed to provide the enantiopure amine derivatives. 10 Inspired by its versatility in asymmetric synthesis, we attempted the total synthesis of solifenacin (1) and N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2) using N-tert-butanesulfinamide as a source of chirality. Following our interest on the use of (R)-tert-butanesulfinamide for the synthesis of chiral amines, 11 we herein report a simple and efficient synthesis of solifenacin (1), an antispasmodic agent via the addition of aryl Grignard reagent to N-sulfinimine.…”

“…Addition of 4-chlorophenylmagnesium bromide to N-sulfinylimine 12 afforded the 4-chlorophenylsulfinamide 13 in 86% yield with ≥93:7 ratio of diastereomers. 14 Scheme 3 Synthesis of N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2 The ratio was determined by 1 H NMR analysis of the crude mixture and the diastereomers were easily separated by column chromatography. An intramolecular cyclization of the major diastereomer 13 (chlorosulfinamide) in the presence of NaH in DMF at room temperature afforded the pure diastereomer 14 in 73% yield.…”