Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen

Abstract

The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.

Synthesis of 6-Aza-bicyclo[3,2,1]octan-3-ones via Vinylogous Imide Photochemistry: An Approach to the Synthesis of the Hetisine Alkaloids

“…We have recently examined the photocycloaddition of the corresponding 1,5-dienes, that is, 5 , and we report herein that these substrates lead to a general synthesis of azabicyclo[3,2,1]octanones, 8 , via the “crossed” photoadduct, 6 . The widespread distribution of the azabicyclo[3,2,1]octanone ring system in molecules of nature, that is, sarain A, 9 , securinine, 10 , and hetisine, 11 , and the importance of this ring system in medicinal chemistry for the development of analgesics and muscarinic antagonists suggests that the photochemistry of 5 should be of comparable utility to that of 1 .

1

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Ene Reductase Enabled Intramolecular β‐C−H Functionalization of Substituted Cyclohexanones for Efficient Synthesis of Bridged Bicyclic Nitrogen Scaffolds

“…As one important class of bridged bicyclic nitrogen scaffolds, the 6‐azabicyclo[3.2.1]octane ring system is frequently observed in naturally occurring and synthetic small molecules, and it is considered a privileged scaffold for drug discovery (Scheme 1c) [6] . Although a number of synthetic strategies have been developed for synthesizing molecules containing this type of ring system, [7] only four synthetic approaches [7g, l, q, r] have been developed to access 6‐azabicyclo[3.2.1]octan‐3‐ones, which can serve as the synthetic intermediates for accessing bioactive natural products and drug candidates, including azaprophen, [8] actinobolamine, [7e] and cocaine analogues [6] (Scheme 1c). Despite their elegant design, these chemical synthetic methods suffer from either multistep synthesis with low efficiency or complex starting materials, and limited substrate scope (Scheme 1d) [7g, l, q, r] .…”

Carbamoyl Radical‐Mediated Synthesis and Semipinacol Rearrangement of β‐Lactam Diols

“…The 6-azabicyclo[3.2.1]octane ring system is found within a range of synthetic[ 8 ]–[ 10 ] and naturally occurring,[ 7 , 11 ]–[ 18 ] biologically active compounds (Figure 1 ). The former include 7 (“azaprophen”), a synthetic muscarinic anatagonist,[ 9 ] and 8 , a synthetic cocaine analogue and inhibitor of dopamine reuptake. [ 10 ] Representative natural products containing the 6-azabicyclo[3.2.1]octane ring system include aphanorphine,[ 7 , 11 ] members of the Securinega alkaloids, for example securinine,[ 12 ] actinobolamine,[ 13 ] members of the hetisine alkaloids, for example nominine,[ 14 ] lyconadin A,[ 15 ] peduncularine,[ 16 ] calyciphilline D[ 17 ] and sarain A.…”