Tropane‐Based Alkaloids as Muscarinic Antagonists for the Treatment of Asthma, Obstructive Pulmonary Disease, and Motion Sickness

DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens

“…Atropine, hyoscyamine, and scopolamine (hyoscine, Figure ) are antagonists of the muscarinic (M) acetylcholine receptors that play an important role in modulating the central nervous system (CNS, Table ). Chemically, they belong to tropane alkaloids, a group of over 200 analogues sharing a common tropane ( N -methyl-8-azabicyclo­[3.2.1]­octane) fragment. − Structurally similar to acetylcholine, hyoscyamine and atropine are esters of tropine and optically active tropic acid. Pure biologically active hyoscyamine is a levorotatory optic isomer ( S )-(−)-hyoscyamine, and atropine is optically inactive (±)-racemate of hyoscyamine. , Scopolamine is an optically and biologically active, racemation-stable ( S )-(−)-isomer whose chemical structure, unlike those of atropine and hyoscyamine, includes the epoxy group in positions 6 and 7 of the tropane ring (Figure ).…”

“…Pure biologically active hyoscyamine is a levorotatory optic isomer (S)-(−)-hyoscyamine, and atropine is optically inactive (±)-racemate of hyoscyamine. 3,4 Scopolamine is an optically and biologically active, racemation-stable (S)-(−)-isomer 5 whose chemical structure, unlike those of atropine and hyoscyamine, includes the epoxy group in positions 6 and 7 of the tropane ring (Figure 1).…”

“…Atropine was extracted from Atropa belladonna (the deadly nightshade, belladonna) as the principally active compound by Mein and then, as a purified substance, by Runge. 3,6,8 The name "tropane" itself originated from the Latin name for this plant, 2,3,8 also called "Atropos" by the ancient Greeks. 9 Hyoscyamine was extracted from Hyoscyamus niger (the black henbane), and scopolamine from Scopolia carniolica (the henbane bell).…”

“…The first attempt to establish the structure of atropine was made by Kraut in 1863, 19 detailing its degradation to tropine and tropic acid. 3 The full synthesis of atropine was reported by Willstaẗter in 1901 20 as a process that starts from cycloheptanone which undergoes a 8-step conversion into cycloheptatriene (Figure 3). Sequential bromination of cycloheptatriene, replacing bromine with dimethylamine and reducing one of the two double links, results in 1dimethylaminocyclohept-4-en, 3,6,18,20 followed by bromination of the remaining double link, creating a ring in 2bromotropane salt that produces tropidine upon reaction with bases.…”

“…3,18,20 Overall, albeit generally complex and with low yield, this atropine synthesis has been critical for proving its chemical structure. In 1917, a new efficient method was proposed by Robinson, 3,6,21 based on three-component condensation of succinaldehyde, methylamine, and acetonedicarboxylic acid (Figure 3). Subsequent reduction of tropinone generates tropine, and its fusion with tropic acid in the presence of hydrogen chloride produces atropine.…”