Physovenines: Efficient Synthesis of (−)‐ and (+)‐Physovenine and Synthesis of Carbarnate Analogues of (−)‐Physovenine. Anticholinesterase Activity and Analgesic Properties of Optically Active Physovenines

Abstract

Column chromatography of easy available (f)-physovenine (2) on cellulose triacetate afforded (-)-and (+)-physovenine (2a and 2b, resp.). Alkaloids 2a, h required for pharmacological testing were prepared from eserolines (3a, b) by an improved procedure. Natural (-)-physovenine (2a) was equally potent in inhibiting AChE and RChE in uitro as natural physostigmine (la), and twice as potent as the unnatural antipode 2b against AChE and 14 times as potent against BChE. Several carbarnate analogs of 2a were at least as potent as the former compound in these assays. None of the compounds tested did bind to different opiate receptor or serotonine receptor preparations. Most of the compounds tested had considerable analgesic activity in the Writhing test.In search of centrally acting agents potentially useful for treating cholinergic disorders, particularly those manifested by Alzheimer's disease, we have embarked on a re-evaluation of the alkaloids from the seeds of Physostigma venenosum [la-]. Two of the alkaloids, (-)-physostigmine (la; see Scheme) and (-)-physovenine (2a), were reported to have potent anti-acetylcholinesterase (AChE) activity when assayed in vitro, measuring inhibition of AChE obtained from human erythrocytes [2], and l a is medically used to reduce intraocular tension in glaucoma, in the treatment of intestinal atony, and in the treatment of urinary retention [3]. Modification of the carbarnate group and of the Me-N(l) group in l a has afforded several potent analogs [4] [5]. We now have extended this research to another study of the lesser known (-)-physovenine (2a) and some of its carbarnate-ester analogs and of the unnatural enantiomer (+)-physovenine (2b). Natural 2a was isolated from the basic extracts of Physostigma venenosum in 1911 [6] and its structure proposed on the basis of spectral data [7] and proven to be correct by a total synthesis of racemate 2 [8]. The (3aS)-configuration of 2a and the (3aR)-configuration of antipode 2b was elaborated by their enantiospecific synthesis from (-)-physiostigmine (la) [9] and (+)-physiostigmine (la), respectively [2].

Phenserine and ring C hetero‐analogues: Drug candidates for the treatment of Alzheimer's disease

“…*07 With the successful optical resolution achieved on a cellulose triacetate column, both enantiomers of physovenine become readily available. 106 Carbamate analogs of physovenine prepared during these investigations, and evalu- ated for inhibition of AChE and BChE, showed that they had similar inhibitory activity as the corresponding physostigmines, and that the phenylcarbamate analog of phenserine showed selectivity for AChE, whereas the carbamate analog of cymserine showed similar selectivity for BChE106 but with virtually no AChE activity. The results elaborated with physovenines support the conclusion that the anionic site of these molecules interacts with the enzymes by forming a hydrogen bond, rather than a salt with a carboxylic acid residue as hereto assumed43 and described in Figure 4.…”

“…35 The Robinson procedure was later used to prepare the unnatural (+)-enantiomer which was found to retain some of the inhibitory activity for AChE, but had lost much of its effect on BChE. 106 Racemic physovenine can now readily be obtained by the total synthesis shown in Figure 8,35 and by the short synthesis from oxindoles prepared by the Julian route shown in Figure 26. *07 With the successful optical resolution achieved on a cellulose triacetate column, both enantiomers of physovenine become readily available.…”

Blood Cholinesterases as Human Biomarkers of Organophosphorus Pesticide Exposure

“…Plasma BChE averaged 8.1 fold the sensitivity to six physovenines as RBC AChE. For compounds not included in this average, one was equally inhibitory, one ((-)-phenylcarbamate) was 62.5 fold more inhibitory to RBC AChE and one ((-)-cumylcarbamate) was 233.9 fold more inhibitory to plasma BChE (Yu et al 1991 ).…”

“…Some physostigmine analogs differentially inhibit either RBC AChE or plasma BChE (Atack et al 1989). Compared to RBC AChE, the usual plasma BChE is differentially inhibited by physovenines and its analogs in vivo in the rat (Yu et al 1991). Plasma BChE averaged 8.1 fold the sensitivity to six physovenines as RBC AChE.…”

An Overview of Phenserine Tartrate, A Novel Acetylcholinesterase Inhibitor for the Treatment of Alzheimers Disease

“…In the case of a simple methylcarbamic group, as in (-)-physostigmine, decarbamylation occurs relatively quickly and results in a short ChE inhibition half-life. For more complex carbamates, whether aryl or alkyl, the decarbamylation rate is slower and the corresponding half-life of inhibition is longer [49][50][51][52]. Contrary to its long enymatic pharmacodynamic action (half life [t1/ 2 ] = 8.25 h), (-)-phenserine is rapidly cleared from the plasma (t1/ 2 = 12.6 minutes), which was one of the features that aided in the compound's further development.…”