Daffodils galanthamine

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

FIGURE 12-29. Icon for the cholinesterase inhibitor galanthamine. This agent is naturally present in snowdrops and daffodils and may also have nicotinic agonist or cholinergic-releasing actions as well as cholinesterase actions. It is also in testing for Alzheimer s disease. 

Galanthamine is a very interesting cholinesterase inhibitor found in snowdrops and daffodils. It may have a dual mechanism of action, matching cholinesterase inhibition with direct nicotinic agonist actions causing acetylcholine release (Fig. 12—29). Early testing in Alzheimer s disease is underway. 

Galanthamine is a phenanthrene-derivative alkaloid of molecular weight 368.43 its structure is shown in Figure 27.2. Galanthamine can be purified from the bulbs of different strains of Narcissus the quantity recovered per 100 mg of dried bulb ranges from 3.9 to 78.7 mg depending on the specific daffodil cultivar used. 

In daffodil plants, galanthamine (147) is biosynthesized from the aminophenols 397, 398, and 399 but not from 343 which is, however, in the same plants a good precursor of haemanthamine (318) and lycorine (1) (Vol. XI, p. 397). These experimental results were interpreted as proving the existence of a definite order of methylation of norbelladine (399) during the biosynthesis of 147. Thus, methylation takes place in the first instance at nitrogen to give 398, later converted into 397. 

The phenanthridine alkaloid lycorine (narcissine, galanthidine) (MD—Phe G5N C6) has a widespread occurrence and inhibits protein synthesis. Like lycorine, the structurally similar alkaloids dihydrolycorinine, haemanthamine, narciclasine, pretazettine and pseudolycorine also inhibit protein synthesis at the level of peptide bond formation. Galanthamine (lycorimine) (Phe C6N C40 C6 ), from daffodil bulbs but also of widespread occurrence, is both a nACh-R allosteric modulator and an inhibitor of AChE. Galanthamine is clinically employed in the treatment of Alzheimer s disease (dementia linked to deficiency in acetylcholine-mediated signalling in the central nervous system). 

Although norbelladine was shown not to be a precursor of galanthamine (101) in King Alfred daffodils, an incorporation of this compound with labels as shown (103), comparable to that for lycorine (104), has been obtained for galanthamine in Leucojum aestivum As expected, the lycorine showed loss of half its tritium. On the other hand, no loss of tritium was apparent in the galanthamine. The latter result suggested that in the biosynthesis of galanthamine conversion of (105) to narwedine (100) was either not reversible or, if so, enzy-mically controlled. 

Narwedine ([a]p - -100°) was reported to be a constituent of Texas daffodils (105). Repetition of this extraction in another laboratory (103) afforded a mixture of ( )-narwedine and (—)-galanthamine after chromatograph3 Recrystallization from benzene gave narwedine ([ Id +32°). Because of the ease of racemization and its resolution phenomenon in the presence of traces of various galanthamine derivatives the sign of optical rotation of the naturally occurring narwedine is unsettled. 

The alkaloid galanthamine (169) has been obtained from various Amaryllidaceae species including daffodils, the red spider lily Lycoris radiata) and the Caucasian snowdrop (Galanthus woronowii). Its effectiveness as a centrally acting, selective, reversible and competitive inhibitor of acetylcholinesterase has resulted in galanthamine being introduced into the clinic in both the USA and Europe for the symptomatic treatment of mild to moderate forms of Alzheimer s disease [57]. These and various other intriguing feamres of this alkaloid have prompted extensive synthetic studies of it [57]. 

In daffodil plants, galanthamine is biosynthesized from compounds 19-21, but not from norbelladine (5) [which is a good precursor of haemanthamine (14) and lycorine (8) in the same plants] (Fig. 33.6). These experiments suggest a definite order of methylation of norbelladine (5) during the biosynthesis of galathamine. In feeding experiments with the plant Leucojum aestivum, [2,4- H2 C-0-methyl]0-methylnorbelladine (13) is a precursor of galanthamine (18) that retains the same ratio as in the precursor. There... 

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