Synthesis, Pharmacological Characterization, and Quantitative Structure−Activity Relationship Analyses of 3,7,9,9-Tetraalkylbispidines:  Derivatives with Specific Bradycardic Activity

Abstract

A series of 3,7,9,9-tetraalkyl-3,7-diazabicyclo[3.3.1]nonane derivatives (bispidines) was synthesized and identified as potential antiischemic agents. Pharmacological experiments in vitro as well as in vivo are described, and the results are listed. For selection of those compounds fitting best to the desired profile of a specific bradycardic antianginal agent--decrease in heart rate without affecting contractility and blood pressure--these results were scored and ranked. Quantitative structure--activity relationship (QSAR) analyses were performed and discussed a posteriori by means of Hansch, nonelementary discriminant and factor analysis to get insight into the molecular features determining the biological profile. Highly significant equations were obtained, indicating hydrophobic and steric effects. Both pharmacological ranking and QSAR considerations showed compound 6 as the optimum within the structural class under investigation. Compound 6 (tedisamil, KC8857) has been selected as the most promising compound and was chosen for further pharmacological and clinical investigations as an antiischemic drug.

Degradation of dichloromethane by bispidine

“…In turn, the pharmacological activity of bispidines is being studied, partly inspired by folk medicine. Pachycarpine is known for its oxytocic properties, and synthetic tedisamil has been clinically tested as a cardiac antiarrthymic agent . 18 F‐labeled bispidines are studied as radioactive tracers for positron emission tomography .…”

A Practical Synthesis of (±)-α-Isosparteine from a Tetraoxobispidine Core

“…Our new approach to the sparteine alkaloids required an efficient synthesis of tetraoxobispidines 4 . Tetraoxobispidines substituted on the methylene bridge are a well-known class of compounds, commonly referred to as “Guareschi imides” in regard to their usual manner of construction via Guareschi condensation. , By contrast, tetraoxobispidines unsubstituted on the methylene bridge are scarcely known; indeed, only the parent compound ( 6 ) has appeared in an isolated report by Guthzeit . Since it proved impossible to prepare 6 by Guareschi condensation, or by a related tactic, we elected to reexamine Guthzeit's long neglected synthesis of 6 from tetraamide 5 .…”

Trimodal Therapy: Combining Hyperthermia with Repurposed Bexarotene and Ultrasound for Treating Liver Cancer

“…This technique enabled the analysis of electronic distribution and feasibility of forming nanoassemblies and prediction of the pharmacological activities. The pharmacological activities of drugs are affected by the electronic distribution on the drug molecules. − The reactivity of a molecule, for example, intermolecular interaction, is controlled by the frontier molecular orbitals (FMO) such as highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO). The HOMO energy indicates the region of molecules, which can donate electrons during the complex formation with proteins or other receptor molecules.…”